Combination therapy comprising a multi-specific binding agent targeting PD-1 / PD-l1 and VEGF / vegfr and a multi-specific binding agent targeting epcam and 4-1BB for cancer treatment

Abstract

The present disclosure relates to combination therapy using a binding agent that binds to (i) PD-1, PD-L1, or both, and (ii) VEGF, VEGF receptor (VEGFR), or both in combination with a binding agent that binds to (i) EpCAM and 4-1BB to reduce or prevent progression of cancer or to treat cancer.

Description

[0001] COMBINATION THERAPY COMPRISING A MULTI-SPECIFIC BINDING AGENT TARGETING PD-1 / PD-L1 AND VEGF / VEGFR AND A MULTI-SPECIFIC BINDING AGENT TARGETING EPCAM AND 4-1BB FOR CANCER TREATMENT

[0002] Technical Field

[0003] The present invention relates to combination therapy using a binding agent that binds to (i) PD-1, PD-Ll, or both, and (ii) VEGF, VEGF receptor (VEGFR), or both in combination with a binding agent that binds to (i) EpCAM and 4-1BB to reduce or prevent progression of cancer or to treat cancer.

[0004] Background

[0005] Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell-cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-Myc, E-FABP, and cyclins A & E. EpCAM can be used as diagnostic marker for various cancers. Also, EpCAM appears to play a role in tumorigenesis and metastasis of carcinomas, and, thus, it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies.

[0006] 4-1BB (4-1BB) is a member of the TNFR family and is a co-stimulatory molecule on CD8+ and CD4+ T cells, regulatory T cells (Tregs), Natural Killer (T) cells (NK[T] cells), B cells and neutrophils. On T cells, 4-1BB is not constitutively expressed, but induced upon T-cell receptor (TCR) activation (for example, on tumor infiltrating lymphocytes [TILs; Gros et al., J. Clin Invest 2014;124(5):2246-59]). Stimulation via its natural ligand 4-1BBL or agonist antibodies leads to signaling using TRAF-2 and TRAF-1 as adaptors. Early signaling by 4-1BB involves K63 poly-ubiquitination reactions that ultimately result in activation of the nuclear factor (NF)-KB and mitogen-activated protein (MAP)-kinase pathways. Signaling leads to increased T-cell co-stimulation, proliferation, cytokine production, maturation and prolonged CD8+ T-cell survival. Agonistic antibodies against 4-1BB have been shown to promote anti-tumor control by T cells in various pre-clinical models (Murillo et al., Clin Cancer Res 2008;14(21):6895-906). Antibodies stimulating 4-1BB can induce survival and proliferation of T cells, thereby enhancing the antitumor immune response. Antibodies stimulating 4-1BB have been disclosed in the prior art, and include urelumab, a human IgG4 antibody (AU 2004279877) and utomilumab, a human IgG2 antibody (Fisher et al., 2012, Cancer Immunol. Immunother. 61: 1721-1733).

[0007] PD-1 and PD-L1 are inhibitory checkpoint molecules regulating the immune system and enabling selftolerance. At the same time inhibitory checkpoint molecules are ideal targets for cancer immunotherapy. In tumor-draining lymph nodes and within the tumor microenvironment, a subset of CD4+ and CD8+ T cells are characterized by the co-expression of multiple TCR-inducible molecules including high levels of programmed cell death 1 (PD-1) (Gros etal., J. Clin Invest 2014;124(5):2246-59; Seifert etal., Cancers (Basel) 12; Simoni etal., Nature 557: 575-579). Upregulation of PD-1 on T cells can contribute to T-cell exhaustion and reduce T-cell activation upon binding to its ligand programmed cell death 1 ligand 1 (PD-L1) (Yu etal., Eur J Pharmacol 881: 173240). PD-L1 expression is often upregulated by tumor cells,particularly in inflamed tumors (Teng, et al., Cancer Res 75: 2139-2145). Thereby, the tumor cells provide an inhibitory signal to the activated T cells through which they can evade T-cell mediated cytotoxicity. Antibodies that block the PD-1 / PD-L1 inhibitory axis can restore T-cell function (Boussiotis eta!., N Engl J Med 375: 1767-1778; Chen eta / ., Nature 541: 321-330).

[0008] Vascular endothelial growth factor (VEGF) is a member of the platelet-derived growth factor family of cystine-knot growth factors, i.e., a group of signal proteins involved in vasculogenesis and angiogenesis. The most studied form of VEGF is VEGF-A. Upon binding to tyrosine kinase receptors (VEGF receptors (VEGFRs)), the VEGFR dimerizes and becomes activated through transphosphorylation. Overexpression of VEGF can lead to excessive angiogenesis, which is the formation of new blood vessels. This can result in various pathological conditions such as tumor growth and metastasis, diabetic retinopathy, and age-related macular degeneration. Drugs which target VEGF (e.g., aflibercept, bevacizumab, ranibizumab, and pegaptanib) can inhibit VEGF and, thus, slow such diseases.

[0009] Each of the above molecules and their associated pathways have been used as targets for cancer therapy; however, despite some promising results response to treatment is not guaranteed and there is therefore an unmet need for improved methods for cancer treatment.

[0010] Summary

[0011] The present inventors have surprisingly found that the combination of a bispecific antibody which antagonizes the PD-1 / PD-L1 interaction and the VEGF / VEGFR interaction and a second bispecific antibody that binds to the antigen EpCAM and agonizes 4-1BB activity provided for a more pronounced, e.g., more than additive or synergistic, anti-cancer effect compared to the administration of either antibody alone. The treatment described herein combines the administration of a first binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, thereby blocking the PD-1 / PD-L1 inhibitory axis and inhibiting the VEGF / VEGFR pathway in cancer cells with a second binding agent comprising (i) a third binding region which binds to the cancer antigen EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity, thereby activating immune cells.

[0012] Thus, in a first aspect, the present disclosure provides a combination of (a) a first binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and (b) a second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

[0013] In a second aspect, the present disclosure provides a combination for use as a medicament, wherein the combination comprises a first binding agent and a second binding agent, wherein (a) the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizesthe PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and (b) the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

[0014] In a related aspect, the present disclosure provides (a) a first a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction and (b) a second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity, for use as a medicament.

[0015] In third aspect, the present disclosure also provides a method of treating cancer in a subject comprising administering to the subject a first binding agent and a second binding agent, wherein: (a) the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and (b) the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

[0016] In a related aspect, the present disclosure also provides a method comprising administering a first binding agent and a second binding agent to a subject wherein: (a) the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and (b) the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

[0017] In a related aspect, the present disclosure provides a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, for use in a method of treating cancer in a subject, the method comprising administering to the subject the binding agent and a further binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

[0018] In a further related aspect, the present disclosure provides a binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity, for use in a method of treating cancer in a subject, the method comprising administering to the subject the binding agent and a further binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii)a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction.

[0019] In a further related aspect, the present disclosure provides (a) a first a binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction and (b) a second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity, for use in a method of treating cancer in a subject, the method comprising administering to the subject the binding agents (a) and (b).

[0020] In a further related aspect, the present disclosure provides a first binding agent and a second binding agent for use in a method of treating cancer in a subject, wherein the method comprises administering to the subject the first binding agent and the second binding agent, wherein the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and wherein the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

[0021] In a fourth aspect, the present disclosure provides a medical preparation, combination, kit, or composition comprising a first binding agent and a second binding agent, wherein: (a) the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and (b) the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

[0022] In a further aspect, the present disclosure provides a kit comprising a first binding agent and a second binding agent, wherein (a) the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and (b) the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity, wherein the first and second binding agents can be in one or more containers / vials.

[0023] In a further related aspect, the present disclosure provides a kit comprising (a) a composition, preferably a pharmaceutical composition, comprising (a) a first binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction; and (b) a composition, preferably a pharmaceutical composition, comprising(b) a second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

[0024] In a further related aspect, the present disclosure provides a kit comprising (a) a first binding agent and a second binding agent; or (b) a first binding agent and instructions for combining the first binding agent with the second binding agent for use in a treatment of cancer; or (c) a second binding agent and instructions for combining the second binding agent with a first binding agent for use in a treatment of cancer in a subject; wherein the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction and / or wherein the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

[0025] In another aspect, the present disclosure provides for use of a binding agent, wherein (a) the binding agent comprises (i) a binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction and (ii) a different binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction for the manufacture of a medicament for treating or preventing a disease or disorder, e.g., cancer, in a subject in combination with another binding agent, wherein the other binding agent comprises (i) a binding region which binds to EpCAM; and (ii) a different binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity. In another aspect, the present disclosure provides for use of a binding agent, wherein the binding agent comprises (i) a binding region which binds to EpCAM; and (ii) a different binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity for the manufacture of a medicament for treating or preventing a disease or disorder, e.g., cancer, in a subject in combination with a another binding agent, wherein (a) the other binding agent comprises (i) a binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction and (ii) a different binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction.Description of the Sequences

[0026] Table 1 - Sequences

[0027] SEQ ID NO: Reference Domain Sequence

[0028] 1 IgGl-EpCAM-A37-FERL VH QVQLVQSGAEVKKPGSSVRVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADE STSTAYMELSSLRSEDTAVYYCARDPFLHYWGQGTLVTVSS

[0029] 2 IgGl-EpCAM-A37-FERL VH_CDR1 GGTFSSYA

[0030] 3 IgGl-EpCAM-A37-FERL VH_CDR2 IIPIFGTA

[0031] 4 IgGl-EpCAM-A37-FERL VH_CDR3 ARDPFLHY

[0032] 5 IgGl-EpCAM-A37-FERL VL EIELTQSPGTLSLSPGERATLSCRASQTISNNYLAWYQQKRGQAPRLLIYAASSRATGIPDRFSGTGSGTDFTLTIS RLEPEDFAVYYCAQGELYPRQFGGGTKLEIK

[0033] 6 IgGl-EpCAM-A37-FERL VL_CDR1 QTISNNY

[0034] 7 IgGl-EpCAM-A37-FERL VL_CDR2 AAS

[0035] 8 IgGl-EpCAM-A37-FERL VL_CDR3 AQGELYPRQ

[0036] 9 IgGl-EpCAM-A37-FERL Full heavy QVQLVQSGAEVKKPGSSVRVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADE chain STSTAYMELSSLRSEDTAVYYCARDPFLHYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEFERGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0037] 10 IgGl-EpCAM-A37- Full light EIELTQSPGTLSLSPGERATLSCRASQTISNNYLAWYQQKRGQAPRLLIYAASSRATGIPDRFSGTGSGTDFTLTISFEAR / IgGl-EpCAM- chain RLEPEDFAVYYCAQGELYPRQFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNA37-FERL ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 11 IgGl-CD137-009- VH EVQLVESGGGLVQPGRSLRLSCTASGFSLNDYWMSWVRQAPGKGLEWVGYIDVGGSLYYAASVKGRFTISRDDS HC7LC2-FEAR KSIAYLQMNSLKTEDTAVYYCARGGLTYGFDLWGQGTLVTVSS

[0038] 12 IgGl-CD137-009- VH_CDR1 GFSLNDYW

[0039] HC7LC2-FEAR

[0040] 13 IgGl-CD137-009- VH_CDR2 IDVGGSL

[0041] HC7LC2-FEAR

[0042] 14 IgGl-CD137-009- VH_CDR3 ARGGLTYGFDL

[0043]

[0044] HC7LC2-FEAR15 IgGl-CD137-009- VL DIVMTQSPSSLSASVGDRVTITCQASEDISSYLAWYQQKPGKAPKRLIYGASDLASGVPSRFSASGSGTDYTFTIS HC7LC2-FEAR SLQPEDIATYYCHYYATISGLGVAFGGGTKVEIK

[0045] 16 IgGl-CD137-009- VL_CDR1 EDISSY

[0046] HC7LC2-FEAR

[0047] 17 IgGl-CD137-009- VL. CDR2 GAS

[0048] HC7LC2-FEAR

[0049] 18 IgGl-CD137-009- VL_CDR3 HYYATISGLGVA

[0050] HC7LC2-FEAR

[0051] 19 IgGl-CD137-009- Full heavy EVQLVESGGGLVQPGRSLRLSCTASGFSLNDYWMSWVRQAPGKGLEWVGYIDVGGSLYYAASVKGRFTISRDDS HC7LC2-FEAR chain KSIAYLQMNSLKTEDTAVYYCARGGLTYGFDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0052] 20 IgGl-CD137-009- Full light DIVMTQSPSSLSASVGDRVTITCQASEDISSYLAWYQQKPGKAPKRLIYGASDLASGVPSRFSASGSGTDYTFTIS HC7LC2-FEAR / chain SLQPEDIATYYCHYYATISGLGVAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKV IgGl-CD137-009- DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC HC7LC2-FEAL

[0053] 21 IgGl-EpCAM-323-A3- Full heavy QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVRQASGEGLKWMGWINTYTGEPTYGEDFKGRFAFSLET FEAL chain SASTAYLQINNLKNEDTATYFCARFGNYVDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTC PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR WSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 22 IgGl-EpCAM-323-A3 / Full light DIVMTQAAFSNPVTLGTSASISCRSSKNLLHSNGITYLYWYLQKPGQSPHLLIYQMSNLASGVPDRFSSSGSGTDF IgGl-EpCAM-323-A3- chain TLRISRVEAEDVGVYYCAQNLEIPRTFGGGTKLEIKRIVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW FEAL / IgGl-EpCAM- KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0054] 323-A3-FEAR

[0055] 23 IgGl-EpCAM-323-A3- Full heavy QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVRQASGEGLKWMGWINTYTGEPTYGEDFKGRFAFSLET FEAR chain SASTAYLQINNLKNEDTATYFCARFGNYVDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTC PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR WSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI

[0056]

[0057] AVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG24 IgGl-EpCAM-323-A3 Full heavy QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVRQASGEGLKWMGWINTYTGEPTYGEDFKGRFAFSLET chain SASTAYLQINNLKNEDTATYFCARFGNYVDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR WSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AVE WESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALH NHYTQKSLSLSPG

[0058] 25 IgGl-EpCAM-UBS-54- Full heavy QVQLVQSGAEVKKPGSSVRVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADE FEAR chain STSTAYMELSSLRSEDTAVYYCARDPFLHYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0059] 26 IgGl-EpCAM-UBS-54- Full light EIELTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLYLGSNRASGVPDRFSGSGSGTDF FEAR chain TLKISRVEAEDVGVYYCMQALQTFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0060] 27 IgGl-EpCAM-C52- Full heavy QVQLVQSGAEVKKPGASVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIVPIFGTANYAQKFQGRVTITADE FEAR chain STSTAYMELSSLRSEDTAVYYCARDPFLHYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0061] 28 IgGl-EpCAM-C52- Full light EIELTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTIS FEAR chain RLEPEDFAVYYCAQGELYPRQFGGGTKLDIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0062] 29 IgGl-EpCAM-A37- Full heavy QVQLVQSGAEVKKPGSSVRVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADE FEAR chain STSTAYMELSSLRSEDTAVYYCARDPFLHYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0063] 30 IgGl-CD137-009- Full heavy EVQLVESGGGLVQPGRSLRLSCTASGFSLNDYWMSWVRQAPGKGLEWVGYIDVGGSLYYAASVKGRFTISRDDS HC7LC2-FEAL chain KSIAYLQMNSLKTEDTAVYYCARGGLTYGFDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD

[0064]

[0065] lAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG31 IgGl-CD137-009-FEAR Full heavy QSLEESGGRLVTPGTPLTLTCTVSGFSLNDYWMSWVRQAPGKGLEWIGYIDVGGSLYYASWAKGRFTISRTSTT chain VDLKMTSLTTEDTATYFCARGGLTYGFDLWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0066] 32 IgGl-CD137-009-FEAR Full light DIVMTQTPASVSEPVGGTVTINCQASEDISSYLAWYQQKPGQRPKRLIYGASDLASGVPSRFSASGSGTEYALTIS chain DLESADAATYYCHYYATISGLGVAFGGGTEVWKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0067] 33 IgGl-CD137-005-FEAR Full heavy QSVEESGGRLVTPGTPLTLTCTASGFTISDFHVTWVRQAPGKGLEWIGTIITSASTTAYATWARGRFTISKSSTTV chain NLKIVSPTTEDTATYFCARSTYTDTSGYYFDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0068] 34 IgGl-CD137-005-FEAR Full light AQVLTQTASPVSAAVGGTVIINCQSSQSIYNGNRLSWYQQKPGQPPKLLIYSASTLASGVSSRFKGSGSGTQFTLA chain ISDVQSDDAATYYCLGSYDCDSADCFAFGGGTEVWERTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0069] 35 IgGl-bl2-FEAR Full heavy QVQLVQSGAEVKKPGASVKVSCQASGYRFSNFVIHWVRQAPGQRFEWMGWINPYNGNKEFSAKFQDRVTFTAD chain TSANTAYMELRSLRSADTAVYYCARVGPYSWDDSPQDNYYMDVWGKGTTVIVSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDK RVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG

[0070] 36 IgGl-bl2-FEAL Full heavy QVQLVQSGAEVKKPGASVKVSCQASGYRFSNFVIHWVRQAPGQRFEWMGWINPYNGNKEFSAKFQDRVTFTAD chain TSANTAYMELRSLRSADTAVYYCARVGPYSWDDSPQDNYYMDVWGKGTTVIVSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDK RVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG

[0071] 37 IgGl-bl2-FEAL / IgGl- Full light EIVLTQSPGTLSLSPGERATFSCRSSHSIRSRRVAWYQHKPGQAPRLVIHGVSNRASGISDRFSGSGSGTDFTLTI bl2-FEAR / IgGl-bl2- chain TRVEPEDFALYYCQVYGASSYTFGQGTKLERKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVD

[0072]

[0073] FERL NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC38 IgGl-bl2-FERL Full heavy QVQLVQSGAEVKKPGASVKVSCQASGYRFSNFVIHWVRQAPGQRFEWMGWINPYNGNKEFSAKFQDRVTFTAD chain TSANTAYMELRSLRSADTAVYYCARVGPYSWDDSPQDNYYMDVWGKGTTVIVSSASTKGPSVFPLAPSSKSTSG GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDK RVEPKSCDKTHTCPPCPAPEFERGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG

[0074] 39 IgG2amm-EpCAM-323- Full heavy QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVRQASGEGLKWMGWINTYTGEPTYGEDFKGRFAFSLET A3-AAKR chain SASTAYLQINNLKNEDTATYFCARFGNYVDYWGQGTTLTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYF PEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSrTCNVAHPASSTKVDKKIEPRGPTIKPCPP CKCPAPNAAGGPSVFIFPPKIKDVLMISLSPMVTCVWDVSEDDPDVQISWFVNNVEVLTAQTQTHREDYNSTLR WSALPIQHQDWMSGKEFKCKVNNKALPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVKDFMPED IYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSRLRVEKKNWVERNSYSCSWHEGLHNHHTTKSFSRTPG

[0075] 40 IgG2amm-EpCAM-323- Full light DIVMTQAAFSNPVTLGTSASISCRSSKNLLHSNGITYLYWYLQKPGQSPHLLIYQMSNLASGVPDRFSSSGSGTDF A3-AAKR / IgG2amm- chain TLRISRVEAEDVGVYYCAQNLEIPRTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASWCFLNNFYPKDINVKW EpCAM-323-A3-AALT KIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC

[0076] 41 IgG2amm-EpCAM-323- Full heavy QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVRQASGEGLKWMGWINTYTGEPTYGEDFKGRFAFSLET A3-AALT chain SASTAYLQINNLKNEDTATYFCARFGNYVDYWGQGTTLTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYF PEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPP CKCPAPNAAGGPSVFIFPPKIKDVLMISLSPMVTCVWDVSEDDPDVQISWFVNNVEVLTAQTQTHREDYNSTLR WSALPIQHQDWMSGKEFKCKVNNKALPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPED IYVEWTNNGKTELNYKNTEPVLDSDGSYLMYSKLTVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG

[0077] 42 IgG2amm-m4-lBB- Full heavy EMQLVESGGGLVQPGRSMKLSCAGSGFTLSDYGVAWVRQAPKKGLEWVAYISYAGGTTYYRESVKGRFTISRDN 3H3-AAKR chain AKSTLYLQMDSLRSEDTATYYCTIDGYGGYSGSHWYFDFWGPGTMVTVSSAKTTAPSVYPLAPVCGDTTGSSVT LGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPR GPTIKPCPPCKCPAPNAAGGPSVFIFPPKIKDVLMISLSPMVTCWVDVSEDDPDVQISWFVNNVEVLTAQTQTHR EDYNSTLRWSALPIQHQDWMSGKEFKCKVNNKALPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCM VKDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSRLRVEKKNWVERNSYSCSWHEGLHNHHTTKSFS RTPG

[0078] 43 IgG2amm-m4-lBB- Full light DIQMTQSPSLLSASVGDRVTLNCRTSQNVYKNLAWYQQKLGEAPKLLIYNANSLQAGIPSRFSGSGSGTDFTLTIS 3H3-AAKR chain SLQPEDVATYFCQQYYSGNTFGAGTNLELKRADAAPTVSIFPPSSEQLTSGGASWCFLNNFYPKDINVKWKIDGS

[0079]

[0080] ERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC44 IgG2amm-bl2-AALT Full heavy QVQLVQSGAEVKKPGASVKVSCQASGYRFSNFVIHWVRQAPGQRFEWMGWINPYNGNKEFSAKFQDRVTFTAD chain TSANTAYMELRSLRSADTAVYYCARVGPYSWDDSPQDNYYMDVWGKGTTVIVSSAKTTAPSVYPLAPVCGDTTG SSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKK IEPRGPTIKPCPPCKCPAPNAAGGPSVFIFPPKIKDVLMISLSPMVTCVWDVSEDDPDVQISWFVNNVEVLTAQT QTHREDYNSTLRWSALPIQHQDWMSGKEFKCKVNNKALPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVT LTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYLMYSKLTVEKKNWVERNSYSCSWHEGLHNHHTT KSFSRTPG

[0081] 45 IgG2amm-bl2-AALT / Full light EIVLTQSPGTLSLSPGERATFSCRSSHSIRSRRVAWYQHKPGQAPRLVIHGVSNRASGISDRFSGSGSGTDFTLTI IgG2amm-bl2-AAKR chain TRVEPEDFALYYCQVYGASSYTFGQGTKLERKRADAAPTVSIFPPSSEQLTSGGASWCFLNNFYPKDINVKWKID GSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC

[0082] 46 IgG2amm-bl2-AAKR Full heavy QVQLVQSGAEVKKPGASVKVSCQASGYRFSNFVIHWVRQAPGQRFEWMGWINPYNGNKEFSAKFQDRVTFTAD chain TSANTAYMELRSLRSADTAVYYCARVGPYSWDDSPQDNYYMDVWGKGTTVIVSSAKTTAPSVYPLAPVCGDTTG SSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKK IEPRGPTIKPCPPCKCPAPNAAGGPSVFIFPPKIKDVLMISLSPMVTCVWDVSEDDPDVQISWFVNNVEVLTAQT QTHREDYNSTLRWSALPIQHQDWMSGKEFKCKVNNKALPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVT LTCMVKDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSRLRVEKKNWVERNSYSCSWHEGLHNHHT TKSFSRTPG

[0083] 47 IgGl constant region ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG

[0084] 48 IgGl-FEA constant with FEA ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG region substitutio TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHED n (bold) PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG

[0085] 49 IgGl-FER constant with FER ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG region substitutio TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFERGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHED n (bold) PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG

[0086] 50 IgGl-F405L constant with ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG region F405L TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHED substitutio PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE n (bold) PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQ

[0087]

[0088] GNVFSCSVMHEALHNHYTQKSLSLSPG51 IgGl-K409R constant with ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG region K409R TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHED substitutio PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE n (bold) PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPG

[0089] 52 IgGl-FEAR constant with FEA ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG region substitutio TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHED n and PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE with PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQ K409R GNVFSCSVMHEALHNHYTQKSLSLSPG

[0090] substitutio

[0091] n (bold)

[0092] 53 IgGl-FEAL constant with FEA ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG region substitutio TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHED n and PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE with PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQ F405L GNVFSCSVMHEALHNHYTQKSLSLSPG

[0093] substitutio

[0094] n (bold)

[0095] 54 IgGl-FERL constant with FER ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG region substitutio TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFERGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHED n and PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE with PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQ F405L GNVFSCSVMHEALHNHYTQKSLSLSPG

[0096] substitutio

[0097] n (bold)

[0098] 55 kappa light chain constant RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK constant region region of ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0099] human

[0100] kappa

[0101] light chain

[0102] 56 lambda light chain constant GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTP constant region region of EQWKSHRSYSCQVTHEGSTVEKTVAPTECS

[0103] human

[0104] lambda

[0105]

[0106] light chain57 IgG2amm-AAKR with AAKR AKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWP substitutio SQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNAAGGPSVFIFPPKIKDVLMISLSPMVTCWVDVSEDD n PDVQISWFVNNVEVLTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKALPAPIERTISKPKGSVRA substitutio PQVYVLPPPEEEMTKKQVTLTCMVKDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSRLRVEKKNWVE n (bold) RNSYSCSWHEGLHNHHTTKSFSRTPG

[0107] 58 IgG2amm-AALT with AALT AKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWP substitutio SQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNAAGGPSVFIFPPKIKDVLMISLSPMVTCVWDVSEDD n PDVQISWFVNNVEVLTAQTQTHREDYNSTLRWSALPIQHQDWMSGKEFKCKVNNKALPAPIERTISKPKGSVRA substitutio PQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYLMYSKLIVEKKNWVE n (bold) RNSYSCSWHEGLHNHHTTKSFSRTPG

[0108] 59 Human EpCAM Full MAPPQVLAFGLLLAAATATFAAAQEECVCENYKLAVNCFVNNNRQCQCTSVGAQNTVTCSKLAAKCIVMKAF length MNGSKLGRRAKPEGALQNNDGLYDPDCDESGLFKAKQCNGTSMCWCVNTAGVRRTDKDTEITCSERVRTYWIII protein ELKHKAREKPYDSKSLRTALQKEITTRYQLDPKFITSILYENNVITIDLVQNSSQKTQNDVDIADVAYYFEKDVKGE sequence SLFHSKKMDLTVNGEQLDLDPGQTLIYYVDEKAPEFSMQGLKAGVIAVIWWIAWAGIWLVISRKKRMAKYEKA with EIKEMGEMHRELNA

[0109] signal

[0110] peptide

[0111] (bold)

[0112] 60 Cynomolgus monkey Full MAPPQVLAFGLLLAAATASFAAAQKECVCENYKLAVNCFLNDNGQCQCTSIGAQNTVLCSKLAAKCIVMKAF EpCAM length MNGSKLGRRAKPEGALQNNDGLYDPDCDESGLFKAKQCNGTSTCWCVNTAGVRRTDKDTEITCSERVRTYWIII protein ELKHKAREKPYDVQSLRTALEEAIKTRYQLDPKFITNILYEDNVITIDLVQNSSQKTQNDVDIADVAYYFEKDVKGE sequence SLFHSKKMDLRVNGEQLDLDPGQTLIYYVDEKAPEFSMQGLKAGVIAVIVVWIAIVAGIWLVISRKKRMAKYEKA with EIKEMGEIHRELNA

[0113] signal

[0114] peptide

[0115] Jbold) _

[0116] 61 Mouse EpCAM Full MAGPQALAFGLLLAWTATLAAAQRDCVCDNYKLATSCSLNEYGEQCQCTSYGTQNTVICSKLASKCLAMKAF length MTHSKSGRRIKPEGAIQNNDGLYDPDCDEQGLFKAKQCNGTATCWCVNTAGVRRTDKDTErTCSERVRTYWIII protein ELKHKERESPYDHQSLQTALQEAFTSRYKLNQKFIKNIMYENNVITIDLMQNSSQKTQDDVDIADVAYYFEKDVK sequence GESLFHSSKSMDLRVNGEPLDLDPGQTLIYYVDEKAPEFSMQGLTAGIIAVIVWSLAVIAGIVVLVISTRKKSAKYE with KAEIKEMGEIHRELNA

[0117] signal

[0118] peptide

[0119]

[0120] (bold)62 Human 4-1BB Full MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICR QCKGVF length RTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKS protein VLVNGTKERDWCGPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSWKRGRKKLLYIF sequence KQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL

[0121] with

[0122] signal

[0123] peptide

[0124] (bold)

[0125] 63 Cynomolgus monkey Full MGNSCYNIVATLLLVLNFERTRSLQDLCSNCPAGTFCDNNRSQICSPCPPNSFSSAGGQRTCDICRQCKGVF 4-1BB length KTRKECSSTSNAECDCISGYHCLGAECSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSV protein LVNGTKERDWCGPSPADLSPGASSATPPAPAREPGHSPQIIFFLALTSTWLFLLFFLVLRFSWKRSRKKLLYIFKQ sequence PFMRPVQTTQEEDGCSCRFPEEEEGGCEL

[0126] with

[0127] signal

[0128] peptide

[0129] (bold)

[0130] 64 IgGl-EpCAM-A37-FERL VH_CDR1 SYAIS

[0131] 65 IgGl-EpCAM-A37-FERL VH_CDR2 GIIPIFGTANYAQKFQG

[0132] 66 IgGl-EpCAM-A37-FERL VHJ2DR3 DPFLHY

[0133] 67 IgGl-EpCAM-A37-FERL VL CDR1 RASQTISNNYLA

[0134] 68 IgGl-EpCAM-A37-FERL VL_CDR2 AASSRAT

[0135] 69 IgGl-CD137-009- VH_CDR1 DYWMS

[0136] HC7LC2-FEAR

[0137] 70 IgGl-CD137-009- VH_CDR2 YIDVGGSLYYAASVKG

[0138] HC7LC2-FEAR

[0139] 71 IgGl-CD137-009- VH_CDR3 GGLTYGFDL

[0140] HC7LC2-FEAR

[0141] 72 IgGl-CD137-009- VL. CDR1 QASEDISSYLA

[0142] HC7LC2-FEAR

[0143] 73 IgGl-CD137-009- VL_CDR2 GASDLAS

[0144] HC7LC2-FEAR

[0145] 74 IgGl-EpCAM-A37-FERL VH_CDR1 SYA

[0146] 75 IgGl-CD137-009- VH_CDR1 DYW

[0147]

[0148] HC7LC2-FEAR76 IgGl-EpCAM-323-A3- VHJ2DR1 GYTFTNYG FEAL (IMGT)

[0149] 77 IgGl-EpCAM-323-A3- VH_CDR2 INTYTGEP

[0150] FEAL (IMGT)

[0151] 78 IgGl-EpCAM-323-A3- VH_CDR3 ARFGNYVDY FEAL (IMGT)

[0152] 79 IgGl-EpCAM-323-A3 / VLJZDRl KNLLHSNGITY IgGl-EpCAM-323-A3- FEAL / IgGl-EpCAM- 323-A3-FEAR (IMGT)

[0153] 80 IgGl-EpCAM-323-A3 / VL_CDR2 QM

[0154] IgGl-EpCAM-323-A3- FEAL / IgGl-EpCAM- 323-A3-FEAR (IMGT)

[0155] 81 IgGl-EpCAM-323-A3 / VLJ2DR3 AQNLEIPRT

[0156] IgGl-EpCAM-323-A3- FEAL / IgGl-EpCAM- 323-A3-FEAR (IMGT)

[0157] 82 IgGl-EpCAM-323-A3- VH_CDR1 NYGMN

[0158] FEAL (Kabat)

[0159] 83 IgGl-EpCAM-323-A3- VH_CDR2 WINTYTGEPTYGEDFKG FEAL (Kabat)

[0160] 84 IgGl-EpCAM-323-A3- VH_CDR3 FGNYVDY

[0161] FEAL (Kabat)

[0162] 85 IgGl-EpCAM-323-A3 / VL. CDR1 RSSKNLLHSNGITYLY IgGl-EpCAM-323-A3- FEAL / IgGl-EpCAM- 323-A3-FEAR (Kabat)

[0163] 86 IgGl-EpCAM-323-A3 / VLJ2DR2 QMSNLAS

[0164] IgGl-EpCAM-323-A3- FEAL / IgGl-EpCAM- 323-A3-FEAR (Kabat)

[0165] 87 IgGl-EpCAM-323-A3- VHJZDRI NYG

[0166] FEAL (IMGT-Kabat

[0167]

[0168] overlap)88 IgGl-EpCAM-UBS-54- VL_CDR1 QSLLHSNGYNY

[0169] FEAR (IMGT)

[0170] 89 IgGl-EpCAM-UBS-54- VL_CDR2 LG

[0171] FEAR (IMGT)

[0172] 90 IgGl-EpCAM-UBS-54- VL_CDR3 MQALQTFT

[0173] FEAR (IMGT)

[0174] 91 IgGl-EpCAM-UBS-54- VLJ2DR1 RSSQSLLHSNGYNYLD

[0175] FEAR (Kabat)

[0176] 92 IgGl-EpCAM-UBS-54- VL CDR2 LGSNRAS

[0177] FEAR (Kabat)

[0178] 93 IgGl-EpCAM-C52- VH_CDR2 IVPIFGTA

[0179] FEAR (IMGT)

[0180] 94 IgGl-EpCAM-C52- VLJ2DR1 QSVSSSY

[0181] FEAR (IMGT)

[0182] 95 IgGl-EpCAM-C52- VL_CDR2 GA

[0183] FEAR (IMGT)

[0184] 96 IgGl-EpCAM-C52- VH_CDR2 GIVPIFGTANYAQKFQG

[0185] FEAR (Kabat)

[0186] 97 IgGl-EpCAM-C52- VLJZDRI RASQSVSSSYLA

[0187] FEAR (Kabat)

[0188] 98 IgGl-EpCAM-C52- VLJ2DR2 GASSRAT

[0189] FEAR (Kabat)

[0190] 99 Atezolizumab Heavy EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADT chain SKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVfflTPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAS TYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0191] 100 Atezolizumab Light DIQMTQSPSSLSASVGDRVTlTCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTIS chain SLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0192] 217 Atezolizumab HCDR1 DSWIH

[0193] (IMGT)

[0194] 218 Atezolizumab HCDR2 WISPYGGSTYYADSVKG

[0195]

[0196] (IMGT)219 Atezolizumab HCDR3 RHWPGGFDY

[0197] (IMGT)

[0198] 220 Atezolizumab LCDR1 RASQDVSTAVA

[0199] (IMGT)

[0200] 221 Atezolizumab LCDR2 SASFLYS

[0201] (IMGT)

[0202] 222 Atezolizumab LCDR3 QQYLYHPAT

[0203] (IMGT)

[0204] 223 Atezolizumab HCDR1 GFTFSDSW

[0205] (Kabat)

[0206] 224 Atezolizumab HCDR2 ISPYGGST

[0207] (Kabat)

[0208] 225 Atezolizumab HCDR3 ARRHWPGGFDY

[0209] (Kabat)

[0210] 226 Atezolizumab LCDR1 QDVSTA

[0211] (Kabat)

[0212] 227 Atezolizumab LCDR2 SAS

[0213] (Kabat)

[0214] 222 Atezolizumab LCDR3 QQYLYHPAT

[0215] (Kabat)

[0216] 228 Atezolizumab VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGR FTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS

[0217] 229 Atezolizumab VL DIQMTQSPSSLSASVGDRVHTCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIK

[0218] 101 IgG2amm-EpCAM-A37- Heavy QVQLVQSGAEVKKPGSSVRVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTTTADE AALT chain STSTAYMELSSLRSEDTAVYYCARDPFLHYWGQGTLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPE PVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCK CPAPNAAGGPSVFIFPPKIKDVLMISLSPMVTCVWDVSEDDPDVQISWFVNNVEVLTAQTQTHREDYNSTLRW SALPIQHQDWMSGKEFKCKVNNKALPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIY VEWTNNGKTELNYKNTEPVLDSDGSYLMYSKLTVEKKNWVERNSYSCSWHEGLHNHHTTKSFSRTPG

[0219] 102 IgG2amm-EpCAM-A37- Light EIELTQSPGTLSLSPGERATLSCRASQTISNNYLAWYQQKRGQAPRLLIYAASSRATGIPDRFSGTGSGTDFTLTIS AALT chain RLEPEDFAVYYCAQGELYPRQFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDG

[0220]

[0221] SERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNECTable 1, continued: Description of the sequences

[0222] Anti-PD-1 antibody Al

[0223] 103 HCDR1 (IMGT) GFAFSSYD

[0224] 104 HCDR2 (IMGT) ISGGGRYT

[0225] 105 HCDR3 (IMGT) ANRYGEAWFAY

[0226] 106 LCDR1 (IMGT) QDINTY

[0227] 107 LCDR2 (IMGT) RAN

[0228] 108 LCDR3 (IMGT) LQYDEFPLT

[0229] 109 HCDR1 (Kabat) SYDMS

[0230] 110 HCDR2 (Kabat) TISGGGRYTYYPDS VKG

[0231] 111 HCDR3 (Kabat) RYGEAWFAY

[0232] 112 LCDR1 (Kabat) RASQDINTYLS

[0233] 113 LCDR2 (Kabat) RANRLVS

[0234] 108 LCDR3 (Kabat) LQYDEFPLT EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSK NNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSM

[0235] 114 scFv fusion

[0236] SASVGDRVTFTCRASQDINTYLSWYQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYC LQYDEFPLTFGAGTKLELKR

[0237] Anti-PD-1 antibody A2

[0238] 115 HCDR1 (Kabat) RNFMG

[0239] 116 HCDR2 (Kabat) AIYTGTSRTYYADSVKG

[0240] 117 HCDR3 a (Kabat) DLRDGFWDTGVWNT

[0241] 118 HCDR3 b (Kabat) DLREGFWDTGVWNT

[0242] 119 HCDR1 (IMGT) GNIYNRNF

[0243] 120 HCDR2 (IMGT) IYTGTSRT

[0244] 121 HCDR3 a (IMGT) AADLRDGFWDTGVWNT

[0245] 122 HCDR3 b (IMGT) AADLREGFWDTGVWNT EVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGREGVSAIYTGTSRTYYADSVKGRFTISRDNAK

[0246] 123 VHH a

[0247] NTVYLQMNSLRPEDTAVYYCAADLRDGFWDTGVWNTWGQGTLVTVSS EVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGLEGVSAIYTGTSRTYYADSVKGRFTISRDNSK

[0248] 124 VHH b

[0249] NTVYLQMNSLRAEDTAVYYCAADLREGFWDTGVWNTWGQGTLVTVSS

[0250] Anti-PD-1 antibody A5

[0251] 185 HCDR1 GFTFSSYMMS

[0252]

[0253] 186 HCDR2 TISGGGSNKYYVDSVKG187 HCDR3 QLYYFDY

[0254] 188 LCDR1 RASQESGIWLS

[0255] 189 LCDR2 TATSLAD

[0256] 190 LCDR3 QQVSVTPFT EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGSNKYYVDSVKGRFTISRDNAK 191 VH

[0257] NSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS DIQMTQSPSSLSASVGDRVTlTCRASQESGIWLSWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSL 192 VL

[0258] QPEDFATYYCQQVSVTPFTFGGGTKVEIK

[0259] Anti-PD-1 antibody A6

[0260] 193 HCDR1 GFTFSSYMMS

[0261] 194 HCDR2 TISGGGSNKYYVDSVKG

[0262] 195 HCDR3 QLYYFDY

[0263] 196 LCDR1 RASQESGIWLS

[0264] 197 LCDR2 AASSLQS

[0265] 198 LCDR3 QQVSVTPFT

[0266] 199 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGSNKYYVDSVKGRFTISRDNAK VH NSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS

[0267] 200 DIQMTQSPSSLSASVGDRVTlTCRASQESGIWLSWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSL VL QPEDFATYYCQQVSVTPFTFGGGTKVEIK

[0268] Anti-PD-1 antibody A7

[0269] 201 HCDR1 GFTFSSYMMS

[0270] 202 HCDR2 TISGGGSNKYYVDSVKG

[0271] 203 HCDR3 QLYYFDY

[0272] 204 LCDR1 RASQESGIWLS

[0273] 205 LCDR2 TASSLAD

[0274] 206 LCDR3 QQVSVTPFT

[0275]

[0276] 207 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGSNKYYVDSVKGRFTISRDNAK VH NSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS

[0277] 208 DIQMTQSPSSLSASVGDRVTlTCRASQESGIWLSWYQQKPGKAPKLLIYTASSLADGVPSRFSGSGSGTDFTLTISSL VL QPEDFATYYCQQVSVTPFTFGGGTKVEIK

[0278] Anti-PD-1 antibody A8

[0279] 209 HCDR1 GFTFSSYMMS

[0280] 210 HCDR2 TISGGGSNKYYVDSVKG

[0281] 211 HCDR3 QLYYFDY

[0282] 212 LCDR1 RASQESGIWLS

[0283] 213 LCDR2 AASSLAD

[0284] 214 LCDR3 QQVSVTPFT

[0285] 215 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGSNKYYVDSVKGRFTISRDNAK VH NSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS

[0286] 216 DIQMTQSPSSLSASVGDRVTlTCRASQESGIWLSWYQQKPGKAPKLLIYAASSLADGVPSRFSGSGSGTDFTLTISSL VL QPEDFATYYCQQVSVTPFTFGGGTKVEIK

[0287] Anti-PD-1 antibody A10

[0288] 230 Anti-PD-1 VH-CDR1 (Kabat) NYDMS

[0289] 231 Anti-PD-1 VH-CDR1 (IMGT) GFVFSNYD

[0290] 232 Anti-PD-1 VH-CDR2 (Kabat) TISGGGGYTYYSDSVKG

[0291] 233 Anti-PD-1 VH-CDR2 (IMGT) ISGGGGYT

[0292] 234 Anti-PD-1 VH-CDR3 (Kabat) PYGHYGFEY

[0293] 235 Anti-PD-1 VH-CDR3 (IMGT) ASPYGHYGFEY

[0294] 143 Common VL-CDR1 (Kabat) SASQDISNYLN

[0295] 149 Common VL-CDR1 (IMGT) QDISNY

[0296] 144 Common VL-CDR2 (Kabat) FTSSLHS

[0297]

[0298] 150 Common VL-CDR2 (IMGT) FTS

[0299] 236 Common VL-CDR3 (Kabat) QQYSTLPWT

[0300] 236 Common VL-CDR3 (IMGT) QQYSTLPWT

[0301] 237 Anti-PD-1 variable EVQLVESGGGLVQPGGSLRLSCAASGFVFSNYDMSWVRQAPGKRLEWVATISGGGGYTYYSDSVKGRFTISRDNAK heavy (VH) domain (humanised) NSLYLQMNSLRAEDTAVYYCASPYGHYGFEYWGQGTLVTVSS _

[0302] 238 Common variable DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL light (VL) domain QPEDFATYYCQQYSTLPWTFGQGTKVEIK

[0303] Anti-PD-Ll antibody A3

[0304] 125 HCDR1 (Kabat) SYWMY

[0305] 126 HCDR2 (Kabat) SINSDSSSTYYRDSVKG

[0306] 127 HCDR3 (Kabat) DPGGYA

[0307] 128 HCDR1 (IMGT) GFTFSSYW

[0308] 129 HCDR2 (IMGT) INSDSSST

[0309] 130 HCDR3 (IMGT) AKDPGGYA EVQLQESGGGLVQPGGSLRLSCAASGFTFSSYWMYWLRQAPGKGLEWVSSINSDSSSTYYRDSVKGRFTISRDNAK

[0310] 131 VHH NTLYLQMNSLKSEDTAVYYCAKDPGGYAKGQGTQVTVSS

[0311] Anti-PD-Ll antibody A4

[0312] 132 HCDR1 GYAFTGYT

[0313] 133 HCDR2 FYPGSGTL

[0314] 134 HCDR3 ARHGTGTLMAMDY

[0315] 135 LCDR1 QSLANSYGNTY _

[0316] 136 LCDR2 GIS

[0317] 137 LCDR3 LQGTHQPPT QVQLVQSGAEVKKPGASVKVSCKASGYAFTGYTIHWVRQAPGQRLEWMGWFYPGSGTLKYSEKFQGRVTITRDKS

[0318] 138 VH

[0319] LSTAYMELSSLRSEDTAVYYCARHGTGTLMAMDYWGQGTLVTVSS DWMTQTPLSLSVTPGQPASISCKSSQSLANSYGNTYLSWYLHKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTDFTL

[0320] 139 VL KISRVEAEDVGVYYCLQGTHQPPTFGQGTKLEIK

[0321] Anti-PD-Ll antibody A9

[0322] 262 HCDR1 (IMGT) DSWIH

[0323] 263 HCDR2 (IMGT) WISPYGGSTYYADSVKG

[0324] 264 HCDR3 (IMGT) RHWPGGFDY

[0325] 265 LCDR1 (IMGT) RASQDVSTAVA

[0326] 266 LCDR2 (IMGT) SASFLYS

[0327]

[0328] 267 LCDR3 (IMGT) QQYLYHPAT268 HCDR1 (Kabat) GFTFSDSW

[0329] 269 HCDR2 (Kabat) ISPYGGST

[0330] 270 HCDR3 (Kabat) ARRHWPGGFDY

[0331] 271 LCDR1 (Kabat) QDVSTA

[0332] 272 LCDR2 (Kabat) SAS

[0333] 267 LCDR3 (Kabat) QQYLYHPAT EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSK

[0334] 273 VH (Atezolizumab)

[0335] NTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSL

[0336] 274 VL (Atezolizumab)

[0337] QPEDFATYYCQQYLYHPATFGQGTKVEIK

[0338] Anti-VEGF antibody 1

[0339] 140 HCDR1 (Kabat) NYGMN

[0340] 141 HCDR2 (Kabat) WINTYTGEPTYAADFKR

[0341] 142 HCDR3 (Kabat) YPHYYGSSHWYFDV

[0342] 143 LCDR1 (Kabat) SASQDISNYLN

[0343] 144 LCDR2 (Kabat) FTSSLHS

[0344] 145 LCDR3 (Kabat) QQYSTVPWT

[0345] 146 HCDR1 (IMGT) GYTFTNYG

[0346] 147 HCDR2 (IMGT) INTYTGEP

[0347] 148 HCDR3 (IMGT) AKYPHYYGSSHWYFDV

[0348] 149 LCDR1 (IMGT) QDISNY

[0349] 150 LCDR2 (IMGT) FTS

[0350] 145 LCDR3 (IMGT) QQYSTVPWT EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS

[0351] 151 VH

[0352] KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSS DIQMTQSPSSLSASVGDRVTTTCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL

[0353] 152 VL

[0354] QPEDFATYYCQQYSTVPWTFGQGTKVEIK ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT

[0355] 153 CHI

[0356] QTYICNVNHKPSNTKVDKKVEPKSC

[0357] 239 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGT CHI var

[0358] QTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN

[0359] 154 Fc STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS

[0360]

[0361] DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 240 Fc varl STYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN

[0362] 241 Fc var2 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN

[0363] 242 Fc var3 ATYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIAATISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA

[0364] 155 CL DYEKHKVYACEVTHQGLSSPVTKSFNRGEC EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK

[0365] 156 Heavy chain THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG DIQMTQSPSSLSASVGDRVTTTCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL

[0366] 157 Light chain QPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0367] Anti- VEGF antibody 2

[0368] 243 Anti-VEGF VH-CDR1 (Kabat) (from

[0369] HYGMN

[0370] modified VH)

[0371] 244 Anti-VEGF VH-CDR1 (IMGT) (from

[0372] GYDFTHYG

[0373] modified VH)

[0374] 141 WINTYTGEPTYAADFKR

[0375] Anti-VEGF VH-CDR2 (Kabat)

[0376] 147 INTYTGEP

[0377] Anti-VEGF VH-CDR2 (IMGT)

[0378] 245 Anti-VEGF VH-CDR3 (Kabat) (from

[0379] YPYYYGTSHWYFDV

[0380] modified VH)

[0381] 246 Anti-VEGF VH-CDR3 (IMGT) (from

[0382] AKYPYYYGTSHWYFDV

[0383] modified VH)

[0384] 143 Common VL-CDR1 (Kabat) SASQDISNYLN

[0385]

[0386] 149 Common VL-CDR1 (IMGT) QDISNY

[0387] 144 Common VL-CDR2 (Kabat) FTSSLHS

[0388] 150 Common VL-CDR2 (IMGT) FTS

[0389] 236 Common VL-CDR3 (Kabat) QQYSTLPWT

[0390] 236 Common VL-CDR3 (IMGT) QQYSTLPWT

[0391] 247 Modified Anti-VEGF variable heavy EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS (VH) domain KSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSS

[0392] 151 Anti-VEGF variable heavy (VH) EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS domain KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSS

[0393] 248 Common variable DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL light (VL) domain QPEDFATYYCQQYSTLPWTFGQGTKVEIK

[0394] 249 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTK CHI TYTCNVDHKPSNTKVDKRV ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ

[0395] 250 Fc FNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF (S228P mutation in the hinge region) YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 155 RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA CL DYEKHKVYACEVTHQGLSSPVTKSFNRGEC VEGFR domains

[0396] SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEA

[0397] 158 Domain 1

[0398] TVNGHLYKTNYLTHRQTNTII DWLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSD

[0399] 159 Domain 2 QGLYTCAASSGLMTKKNSTFVRVHEK SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEA

[0400] 160 Domain 3a

[0401] TVNGHLYKTNYLTHRQTNT

[0402] 251 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISAATYKEIGLLTCEA Domain 3b

[0403] TVNGHLYKTNYLTHRQTNT SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEA

[0404] 161 Domain 4 (Fusion 1) TVNGHLYKTNYLTHRQTNTHDWLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQ

[0405]

[0406] SGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEA TVNGHLYKTNYLTHRQTNTIIDWLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQ SGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL

[0407] 162 Domain 5 (Fusion 2) MISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK

[0408] Bispecific antibody PD-L1 x VEGF (Cl)

[0409] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST

[0410] 163 HC VHH fusion YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSG GGGSGEVQLQESGGGLVQPGGSLRLSCAASGFTFSSYWMYWLRQAPGKGLEWVSSINSDSSSTYYRDSVKGRFTIS RDNAKNTLYLQMNSLKSEDTAVYYCAKDPGGYAKGQGTQVTVSS DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL

[0411] 157 LC QPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0412] Bispecific antibody PD-1 x VEGF (C2a)

[0413] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI 164 HC scFv fusion

[0414] AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGS GGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTY YPDSVKGRFTISRDNSKN N LYLQM N SLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSSGGGGSGGGGSGGGGS GGGGSDIQMTQSPSSMSASVGDRVFFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDY

[0415] RLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKR DIQMTQSPSSLSASVGDRVnTCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0416] 157 LC

[0417]

[0418] Bispecific antibody PD-1 x VEGF (C2b)

[0419] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI

[0420] 165 HC VHH fusion AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGS GGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGREGVSAIYTGTSRTYY ADSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAADLRDGFWDTGVWNTWGQGTLVTVSSGGGGSGGGGS GGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGREGVSAIYTGTSRTYYADSVK GRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAADLRDGFWDTGVWNTWGQGTLVTVSS DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL

[0421] 157 LC QPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0422] Bispecific antibody PD-1 x VEGF (C2c)

[0423] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST

[0424] 166 HC VHH fusion

[0425] YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSG GGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGREGVSAIYTGTSRTYYA DSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAADLRDGFWDTGVWNTWGQGTLVTVSS DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL157 LC QPEDFA’TYYCQQYSTVPWTFGQGTKVEIKR'TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0426] Bispecific antibody PD-1 x VEGF (C2d)

[0427] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST

[0428] 167 HC VHH fusion

[0429] YRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSG GGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGLEGVSAIYTGTSRTYYA

[0430]

[0431] DSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAADLREGFWDTGVWNTWGQGTLVTVSSDIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL 157 LC QPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0432] Bispecific antibody PD-1 x VEGF (C2e)

[0433] DIQMTQSPSSLSASVGDRVnTCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL 252 Common light chain for bispecific QPEDFATYYCQQYSTLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQ

[0434] antibody SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC EVQLVESGGGLVQPGGSLRLSCAASGFVFSNYDMSWVRQAPGKRLEWVATISGGGGYTYYSDSVKGRFTISRDNAK NSLYLQMNSLRAEDTAVYYCASPYGHYGFEYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVGGGGSGGGGSGGG

[0435] Heavy chain for bispecific antibody GSEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLD 253 (anti-PD-1 x anti-VEGF orientation) TSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALG CLVKDYFPEPVTV5WNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKnSKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0436] Bispecific antibody PD-1 x VEGF (C2f)

[0437] DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL

[0438] 252 Common light chain for bispecific QPEDFATYYCQQYSTLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQ

[0439] antibody SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTS KSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVGGGGSG

[0440] Heavy chain for bispecific antibody GGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFVFSNYDMSWVRQAPGKRLEWVATISGGGGYTYYSDSVKG 254 (anti-VEGF x anti-PD-1 orientation) RFTISRDNAKNSLYLQMNSLRAEDTAVYYCASPYGHYGFEYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKnSKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK Bispecific antibody PD-1 x VEGF (C2g)

[0441] DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSL252 Common light chain for bispecific QPEDFATYYCQQYSTLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQantibody

[0442]

[0443] SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECEVQLVESGGGLVQPGGSLRLSCAASGFVFSNYDMSWVRQAPGKRLEWVATISGGGGYTYYSDSVKGRFTISRDNAK NSLYLQMNSLRAEDTAVYYCASPYGHYGFEYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVGGGGSGGGGSGGG

[0444] Heavy chain for bispecific antibody GSEVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLD 255 (anti-PD-1 x anti-VEGF orientation; TSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALG including modified VEGF variable CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG heavy (VH) domain) PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0445] Bispecific fusion protein PD-L1 x VEGFR (C3a)

[0446] SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEA TVNGHLYKTNYLTHRQTNTGGSGGSGGSGGSGGSQVQLVQSGAEVKKPGASVKVSCKASGYAFTGYTIHWVRQAP GQRLEWMGWFYPGSGTLKYSEKFQGRVTITRDKSLSTAYMELSSLRSEDTAVYYCARHGTGTLMAMDYWGQGTLV HC fused to VEGFR domain (N TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSS 168

[0447] terminus) SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPG DWMTQTPLSLSVTPGQPASISCKSSQSLANSYGNTYLSWYLHKPGQSPQLUYGISNRFSGVPDRFSGSGSGTDFTL

[0448] 169 FP LC KISRVEAEDVGVYYCLQGTHQPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0449] Bispecific fusion protein PD-L1 x VEGFR (C3b)

[0450] QVQLVQSGAEVKKPGASVKVSCKASGYAFTGYTIHWVRQAPGQRLEWMGWFYPGSGTLKYSEKFQGRVTITRDKS LSTAYMELSSLRSEDTAVYYCARHGTGTLMAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT HC fused to VEGFR domain (C CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 170

[0451] terminus) VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGSGGS GGSGGSSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEI GLLTCEATVNGHLYKTNYLTHRQTNT DWMTQTPLSLSVTPGQPASISCKSSQSLANSYGNTYLSWYLHKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTDFTL KISRVEAEDVGVYYCLQGTHQPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0452] 169 FP LC

[0453]

[0454] Bispecific fusion protein PD-L1 x VEGFR (C3c)

[0455] SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISAATYKEIGLLTCEA TVNGHLYKTNYLTHRQTNTGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQA PGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVT 256 HC fused to VEGFR domain (N VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS terminus) LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNATYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIAATISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVM H EALH NHYTQKSLSLSPG DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSL

[0456] 257 FP LC QPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0457] Bispecific fusion protein PD-L1 x VEGFR (C3d)

[0458] SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISAATYKEIGLLTCEA TVNGHLYKTNYLTHRQTNTGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQA PGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVT

[0459] 258 HC fused to VEGFR domain (N VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSS terminus) LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNATYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIAATISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK DIQMTQSPSSLSASVGDRVTTTCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSL

[0460] 257 FP LC QPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0461] Bispecific fusion protein PD-1 x VEGF (C4a)

[0462] EVQLVESGGGLVQPGGSLRLSCAISGFSLAATDIDWVRQAPGKGLEWVARIFSPSDFTDYADSVKGRFTISADTSKN TVYLQMNSLRAEDTAVYYCGRPDTYAYNIFLDTPTYNALHYRGQGTLVTVSSGGGGSGGGGSGGGGSQGQLVQSG HC: AEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPIHGLEWIGVIESETGGTAYNQKFKGRVTTTADKSTSTAYMELSS 275 LRSEDTAVYYCAREGITTVATTYYWYFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV VHVEGF-linker-VHPD-l-CHl-hinge- TYSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL CH2-CH3 GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQ

[0463] DWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

[0464]

[0465] NNYKTTPPVLDSDGSFFLYSRLIVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKLC: DWMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFT 276 LKISRVEAEDVGVYYCFQGSHVPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVVLPD-l-CL DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0466] Bispecific fusion protein PD-1 x VEGF (C4b)

[0467] QGQLVQSGAEVKKPGASVKVSCKASGYFTDYEMHWVRQAPIHGLEWIGVIESETGGTAYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAREGITVATTYYWYFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL HC: VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP 277 CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VHPD-1 -CH 1 -hinge-CH2-CH3-linker- VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE VHVEGF WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGSGGGGS GGGGSEVQLVESGGGLVQPGGSLRLSCAISGFSLAATDIDWVRQAPGKGLEWVARIFSPSDFTDYADSVKGRFTISA DTSKNTVYLQMNSLRAEDTAVYYCGRPDTYAYNIFLDTPTYNALHYRGQGTLVTVSS LC: DWMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFT 276 LKISRVEAEDVGVYYCFQGSHVPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKV VLPD-l-CL DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0468] Bispecific fusion protein PD-1 x VEGF (C4c)

[0469] QGQLVQSGAEVKKPGASVKVSCKASGYFTDYEMHWVRQAPIHGLEWIGVIESETGGTAYNQKFKGRVTITADKST STAYMELSSLRSEDTAVYYCAREGITWATTYYWYFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL HC: VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVGGGGSG 278 GGGSGGGGSGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VHPD-l-CHl-linker-VHVEGF-linker- VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGSESKYGPPCP hinge-CH2-CH3 PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK LC: DWMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNIYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFT 276 LKISRVEAEDVGVYYCFQGSHVPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKV VLPD-l-CL DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0470] Bispecific fusion protein PD-1 x VEGF (C4d)

[0471] EVQLVESGGGLVQPGGSLRLSCAISGFSLAATDIDWVRQAPGKGLEWVARIFSPSDFTDYADSVKGRFTISADTSKN LC: TVYLQMNSLRAEDTAVYYCGRPDTYAYNIFLDTPTYNALHYRGQGTLVTVSSGGGGSGGGGSGGGGSDWMTQSP 279 LSLPVTLGQPASISCRSSQSIVHSNGN7YLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAE VHVEGF-linker-VLPD-l-CL DVGVYYCFQGSHVPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGN

[0472]

[0473] SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECQGQLVQSGAEVKKPGASVKVSCKASGYFTDYEMHWVRQAPIHGLEWIGVIESETGGTAYNQKFKGRVTITADKST STAYMELSSLRSEDTAVYYCAREGYTTVATTYYWYFDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL HC:

[0474] 280 VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP VHPD-l-CHl-hinge-CH2-CH3 CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0475] Linker for bispecific antibodies

[0476] 171 Linker a GGGGSGGGGSG

[0477] 172 Linker b GGGGSGGGGSGGGGSGGGGS

[0478] 173 Linker c GGSGGSGGSGGSGGS

[0479] 259 Linker d GGGGSGGGGSGGGGS

[0480] PD-1, PD-L1, VEGF, VEGFR

[0481] MQIPQAPWPWWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLWTEGDNATFTCSFSNTSESFVLNWYRMSPSN QTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSWRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEV

[0482] 174 PD-1 PTAHPSPSPRPAGQFQTLWGWGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDF QWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL MQIPQAPWPWWAVLQLGWRPGWFLDSPDRPWNPPTFFPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSN QTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSWRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEV

[0483] 175 PD-1 isoform 1

[0484] PTAHPSPSPRPAGQFQTLWGWGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDF QWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL MQIPQAPWPWWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLWTEGDNATFTCSFSNTSESFVLNWYRMSPSN QTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSWRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEV

[0485] 176 PD-1 isoform 2

[0486] PTAHPSPSPRSAGQFQTLWGWGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDF QWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL MRIFAVFIFMTYWHLLNAFTVTVPKDLYWEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQ HSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILWDPVTSEHELT

[0487] 177 PD-L1

[0488] CQAEGYPKAEVIWTSSDHQVLSGKI 1 1 1 NSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAH PPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET MRIFAVFIFMTYWHLLNAPYNKINQRILWDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKI 1 1 I NSKREEKLF 178 PD-L1 isoform 1 NVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKK CGIQDTNSKKQSDTHLEET MRIFAVFIFMTYWHLLNAPYNKINQRILWDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTrnMSKREEKLF 179 PD-L1 isoform 2 NVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKK

[0489]

[0490] CGIQDTNSKKQSDTHLEETMRIFAVFIFMTYWHLLNAFTVTVPKDLYWEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQ 180 PD-L1 isoform 3 HSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELT CQAEGYPKAEVIWTSSDHQVLSGD

[0491] 181 ^EGF MNFLLSWVHWSLALLLYLHHAK MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGCSRFGGAWRAGEAEP SGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEAAVCADSAPAARAPQALARASGRGGRVAR RGAEESGPPHSPSRRGSASRAGPGRASETM N FLLSWVH WSLALLLYLHHAKWSQAAPMAEGGGQNH HEWKFM D

[0492] 182 VEGF-A VYQRSYCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFL QHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKA RQLELNERTCRCDKPRR MQSKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVT ECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGWYITENKNKTVVIPCLGSISN LNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIWWGYRIYDWLSPSHGIE LSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSG LMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLT1MEVSE RDTGNYTVILTNPISKEKQSHWSLWYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECAN EPSQAVSVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVISF HVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNATMFSNST

[0493] 260 NDILIMELKNASLQDQGDYVCLAQDRKTKKRHCWRQLTVLERVAPNITGNLENQTTSIGESIEVSCTASGNPPPQIM Human VEGFR2 domain

[0494] WFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLEIIILVGTAVIAMFF WLLLVIILRTVKRANGGELKTGYLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGI DKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNWNLLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNE FVPYKTKGARFRQGKDYVGAIPVDLKRRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTLEHLICYSFQVA KGMEFLASRKCIHRDLAARNILLSEKNWKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSF GVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHLGNLLQAN AQQDGKDYIVLPISETLSMEEDSGLSLPTSPVSCMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPLE EPEVKVIPDDNQTDSGMVLASEELKTLEDRTKLSPSFGGMVPSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYSSE

[0495]

[0496] EAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPVMASKVLLVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVT ECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGWYITENKNKTVVIPCLGSISN LNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVWGYRIYDWLSPSHGIE ELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASS GLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPVKYLGYPPPEIKWYKNGIPLESNHTVKVGHVLT1MEVS ERDTGNYTVILTNPISKEKQSHWSLWYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECP NEPSQAVSVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVIS FHVTRGPEITLQPDLQPTEQESVSLWCTADKSTFENLTWYKLGPQPLPVHVGELPTPVCKNLDTLWKLNATIFSNST

[0497] 261 NDILIMELKNASLQDQGDYVCVAQDRKTKKRHCWRQLTVLERVAPMITGNLENQTTSIGETIEVSCTASGNPPPQI Macaca VEGFR2 domain

[0498] MWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLEIIILVGTAVIAN1F FWLLLVIILRTVKRANGGELKTGYLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFG IDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNWNLLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRN EFVPYKTKGARFRQGKDYVGAIPVDLKRRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTLEHLICYSFQV AKGMEFLASRKCIHRDLAARNILLSEKNWKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVW SFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHLGNLLQA NAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVSCMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPL EEPEVKVIPDDNQTDSGMVLASEELKTLEDRTKLAPSFSGMVSSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYSS EEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV EVQLVESGGGLVQPGGSLRLSCAASGFSISGSWIFWVRQAPGKGLEWVGAIWPFGGYTHYADSVKGRFTISADTSK NTAYLQMNSLRAEDTAVYYCARWGHSTSPWAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQIYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR

[0499] hlgGl-mPD-LlxmVEGF-A Full heavy WSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKmSKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV 183

[0500] chain EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGG GSGEVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKCLEWVAWISPYGGSTYYADSVKGRFTISAD TSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGDIQMTQS PSSLSASVGDRVTTTCRASQDVSTAVAWYYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSL QPEDFAT YYCQQYLYHPATFGCGTKVEIK DIQMTQSPSSLSASVGDRVTTTCRASQGVRTSLAWYQQKPGKAPKLLIYDASSLASGVPSRFSGSGSGTDFTLTISSL

[0501] hlgGl-mPD-LlxmVEGF-A

[0502] 184 QPEDFATYYCQQSYKSPLTFGQGTKVEIKRR7VAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNAL Full heavy chain

[0503]

[0504] QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDetailed Description

[0505] Although the present disclosure is further described in more detail below, it is to be understood that this disclosure is not limited to the particular methodologies, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. In the following, the elements of the present disclosure will be described in more detail. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present disclosure to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise. For example, if in a preferred embodiment of the first binding agent used herein the first binding agent comprises one or two anti-PD-Ll single domain antibodies (e.g., one or two anti-PD-Ll VHHs) and in another preferred embodiment of the first binding agent used herein the first binding agent comprises a second binding region which binds to VEGF-A, then in a further preferred embodiment of the first binding agent used herein the first binding agent comprises one or two anti-PD-Ll single domain antibodies (e.g., one or two anti-PD-Ll VHHs) and a second binding region which binds to VEGF-A.

[0506] Preferably, the terms used herein are defined as described in " A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", H. G. W. Leuenberger, B. Nagel, and H. Kolbl, Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

[0507] The practice of the present disclosure will employ, unless otherwise indicated, conventional chemistry, biochemistry, cell biology, immunology, and recombinant DNA techniques which are explained in the literature in the field (cf., e.g., Organikum, Deutscher Verlag der Wissenschaften, Berlin 1990; Streitwieser / Heathcook, " Organische Chemie", VCH, 1990; Beyer / Walter, " Lehrbuch der Organischen Chemie", S. Hirzel Verlag Stuttgart, 1988; Carey / Sundberg, " Organische Chemie", VCH, 1995; March, " Advanced Organic Chemistry", John Wiley & Sons, 1985; Rompp Chemie Lexikon, Falbe / Regitz (Hrsg.), Georg Thieme Verlag Stuttgart, New York, 1989; Molecular Cloning: A Laboratory Manual, 2nd Edition, J. Sambrook etal. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989.

[0508] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g., "such as"), provided herein is intended merely to better illustrate the present disclosure and does not pose a limitation on the scope of the present disclosure otherwise claimed. No languagein the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure.

[0509] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0510] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0511] Citation of documents and studies referenced herein is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the correctness of the contents of these documents.

[0512] Definitions

[0513] In the following, definitions will be provided which apply to all aspects of the present disclosure. The following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings.

[0514] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated member, integer or step or group of members, integers or steps but not the exclusion of any other member, integer or step or group of members, integers or steps. The term "consisting essentially of means excluding other members, integers or steps of any essential significance. The term "comprising" encompasses the term "consisting essentially of which, in turn, encompasses the term "consisting of". Thus, at each occurrence in the present application, the term "comprising" may be replaced with the term "consisting essentially of or "consisting of. Likewise, at each occurrence in the present application, the term "consisting essentially of may be replaced with the term "consisting of.

[0515] The terms "a", "an" and "the" and similar references used in the context of describing the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context.

[0516] Where used herein, "and / or" is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, " X and / or Y" is to be taken as specific disclosure of each of (i) X, (ii) Y, and (iii) X and Y, just as if each is set out individually herein.In the context of the present disclosure, the term "about" denotes an interval of accuracy that the person of ordinary skill will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, and for example ±0.01%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect.

[0517] The term "binding agent" in the context of the present disclosure refers to any agent capable of binding to desired antigens. In certain embodiments, the binding agent is an antibody, antibody fragment, or construct thereof. The binding agent may also comprise synthetic, modified or non-naturally occurring moieties, in particular non-peptide moieties. Such moieties may, for example, link desired antigenbinding functionalities or regions such as antibodies or antibody fragments. In one embodiment, the binding agent is a synthetic construct comprising antigen-binding CDRs or variable regions.

[0518] The term "immunoglobulin" relates to proteins of the immunoglobulin superfamily, preferably to antigen receptors such as antibodies or the B cell receptor (BCR). The immunoglobulins are characterized by a structural domain, i.e., the immunoglobulin domain, having a characteristic immunoglobulin (Ig) fold. The term encompasses membrane bound immunoglobulins as well as soluble immunoglobulins. Membrane bound immunoglobulins are also termed surface immunoglobulins or membrane immunoglobulins, which are generally part of the BCR. Soluble immunoglobulins are generally termed antibodies.

[0519] The structure of immunoglobulins has been well characterized. See, e.g., Fundamental Immunology Ch.

[0520] 7 (Paul, W., ed., 2nded. Raven Press, N. Y. (1989)). Briefly, immunoglobulins generally comprise several chains, typically two identical heavy chains and two identical light chains which are linked via disulfide bonds. These chains are primarily composed of immunoglobulin domains or regions, such as the VL or VL (variable light chain) domain / region, CL or CL (constant light chain) domain / region, VH or VH (variable heavy chain) domain / region, and the CH or CH (constant heavy chain) domains / regions CHI (CHI), CH2 (CH2), CH3 (CH3), and CH4 (CH4). The heavy chain constant region typically is comprised of three domains, CHI, CH2, and CH3. The hinge region is the region between the CHI and CH2 domains of the heavy chain and is highly flexible. Disulfide bonds in the hinge region are part of the interactions between two heavy chains in an IgG molecule. Each light chain typically is comprised of a VL and a CL. The light chain constant region typically is comprised of one domain, CL. The VH and VL regions may be further subdivided into regions of hypervariability (or hypervariable regions which may be hypervariable in sequence and / or form of structurally defined loops), also termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each VH and VL is typically composed of three CDRs and four FRs, arranged from aminoterminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk, J. Mol. Biol. 196, 901-917 (1987)). Unless otherwise stated or contradicted by context,CDR sequences herein are identified according to Kabat or IMGT rules using DomainGapAlign (Lefranc MP., Nucleic Acids Research 1999;27:209-212 and Ehrenmann F., Kaas Q. and Lefranc M.-P. Nucleic Acids Res., 38, D301-307 (2010); see also internet http address www.imgt.org.

[0521] The following table shows the results of determining CDR sequences according to the IMGT rules and the Kabat rules, for example, in relation to SEQ ID NO: 1 and SEQ ID NO: 5 or SEQ ID NO: 11 and SEQ ID NO: 15, and also shows the overlap of the determined CDR sequences.

[0522] CDR sequences of SEQ ID NO: 1 [SEQ ID NOs in brackets]

[0523] IMGT Kabat Overlap

[0524] HCDR1 GGTFSSYA [2] SYAIS

[0064] SYA

[0074]

[0525] HCDR2 IIPIFGTA [3] GIIPIFGTANYAQKFQG IIPIFGTA [3]

[0526]

[0065]

[0527] HCDR3 ARDPFLHY [4] DPFLHY

[0066] DPFLHY

[0066]

[0528] CDR sequences of SEQ ID NO: 5 [SEQ ID Nos in brackets]

[0529] LCDR1 QTISNNY [6] RASQTISNNYLA

[0067] QTISNNY [6] LCDR2 AAS [7] AASSRAT

[0068] AAS [7]

[0530] LCDR3 AQGELYPRQ [8] AQGELYPRQ [8] AQGELYPRQ [8]

[0531]

[0532] CDR sequences of SEQ ID NO: 11 [SEQ ID NOs in brackets]

[0533] IMGT Kabat Overlap

[0534] HCDR1 GFSLNDYW

[0012] DYWMS

[0069] DYW

[0075]

[0535] HCDR2 IDVGGSL

[0013] YIDVGGSLYYAASVKG IDVGGSL

[0013]

[0536]

[0070]

[0537] HCDR3 ARGGLTYGFDL

[0014] GGLTYGFDL

[0071] GGLTYGFDL

[0071] CDR sequences of SEQ ID NO: 15 [SEQ ID Nos in brackets]

[0538] LCDR1 EDISSY

[0016] QASEDISSYLA

[0072] EDISSY

[0016] LCDR2 GAS

[0017] GASDLAS

[0073] GAS

[0017]

[0539] LCDR3 HYYATISGLGVA

[0018] HYYATISGLGVA

[0018] HYYATISGLGVA

[0018]

[0540]

[0541] The following table shows the results of determining CDR sequences according to the IMGT rules and the Kabat rules, for example, in relation to SEQ ID NO: 21 and SEQ ID NO: 22, and also shows the overlap of the determined CDR sequences.

[0542] CDR sequences of SEQ ID NO: 21 [SEQ ID NOs in brackets]

[0543] IMGT Kabat Overlap

[0544] HCDR1 GYTFTNYG

[0076] NYGMN

[0082] NYG

[0087]

[0545] HCDR2 INTYTGEP

[0077] WINTYTGEPTYGEDFKG INTYTGEP

[0077]

[0546]

[0083]

[0547]

[0548] HCDR3 ARFGNYVDY

[0078] FGNYVDY

[0084] FGNYVDY

[0084] CDR sequences of SEQ ID NO: 22 [SEQ ID Nos in brackets]

[0549] LCDR1 KNLLHSNGITY

[0079] RSSKNLLHSNGITYLY KNLLHSNGITY

[0079]

[0550]

[0085]

[0551] LCDR2 QM

[0080] QMSNLAS

[0086] QM

[0080]

[0552] LCDR3 AQNLEIPRT

[0081] AQNLEIPRT

[0081] AQNLEIPRT

[0081]

[0553]

[0554] The following table shows the results of determining CDR sequences according to the IMGT rules and the Kabat rules, for example, in relation to SEQ ID NO: 25 and SEQ ID NO: 26, and also shows the overlap of the determined CDR sequences.

[0555] CDR sequences of SEQ ID NO: 25 [SEQ ID NOs in brackets]

[0556] IMGT Kabat Overlap

[0557] HCDR1 GGTFSSYA [2] SYAIS

[0064] SYA

[0074]

[0558] HCDR2 IIPIFGTA [3] GIIPIFGTANYAQKFQG IIPIFGTA [3]

[0559]

[0065]

[0560] HCDR3 ARDPFLHY [4] DPFLHY

[0066] DPFLHY

[0066]

[0561] CDR sequences of SEQ ID NO: 26 [SEQ ID Nos in brackets]

[0562] LCDR1 QSLLHSNGYNY

[0088] RSSQSLLHSNGYNYLD QSLLHSNGYNY

[0088]

[0563]

[0091]

[0564] LCDR2 LG

[0089] LGSNRAS

[0092] LG

[0089]

[0565] LCDR3 MQALQTFT

[0090] MQALQTFT

[0090] MQALQTFT

[0090]

[0566]

[0567] The following table shows the results of determining CDR sequences according to the IMGT rules and the Kabat rules, for example, in relation to SEQ ID NO: 27 and SEQ ID NO: 28, and also shows the overlap of the determined CDR sequences.

[0568] CDR sequences of SEQ ID NO: 27 [SEQ ID NOs in brackets]

[0569] IMGT Kabat Overlap

[0570] HCDR1 GGTFSSYA [2] SYAIS

[0064] SYA

[0074]

[0571] HCDR2 IVPIFGTA

[0093] GIVPIFGTANYAQKFQG IVPIFGTA

[0093]

[0572]

[0096]

[0573] HCDR3 ARDPFLHY [4] DPFLHY

[0066] DPFLHY

[0066] CDR sequences of SEQ ID NO: 28 [SEQ ID Nos in brackets]

[0574] LCDR1 QSVSSSY

[0094] RASQSVSSSYLA

[0097] QSVSSSY

[0094] LCDR2 GA

[0095] GASSRAT

[0098] GA

[0095]

[0575] LCDR3 AQGELYPRQ [8] AQGELYPRQ [8] AQGELYPRQ [8]

[0576]

[0577] Unless otherwise stated or contradicted by context, reference to amino acid positions in the constant regions in the present disclosure is according to the EU-numbering (Edelman etal., Proc Natl Acad Sci USA. 1969 May;63(l):78-85; Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition. 1991 NIH Publication No. 91-3242).

[0578] There are five types of mammalian immunoglobulin heavy chains, i.e., a, 8, E, y, and p which account for the different classes of antibodies, i.e., IgA, IgD, IgE, IgG, and IgM. As opposed to the heavy chains of soluble immunoglobulins, the heavy chains of membrane or surface immunoglobulins comprise a transmembrane domain and a short cytoplasmic domain at their carboxy-terminus. In mammals there are two types of light chains, i.e., lambda and kappa. The immunoglobulin chains comprise a variable region and a constant region. The constant region is essentially conserved within the different isotypes of the immunoglobulins, wherein the variable part is highly divers and accounts for antigen recognition. The term "amino acid" and "amino acid residue" may herein be used interchangeably, and are not to be understood limiting. Amino acids are organic compounds containing amine (-NH2) and carboxyl (-COOH) functional groups, along with a side chain (R group) specific to each amino acid. In the context of the present disclosure, amino acids may be classified based on structure and chemical characteristics. Thus, classes of amino acids may be reflected in one or both of the following tables:

[0579] Table 2: Main classification based on structure and general chemical characterization of R group Class Amino acid

[0580] Acidic Residues D and E

[0581] Basic Residues K, R, and H

[0582] Hydrophilic Uncharged Residues S, T, N, and Q

[0583] Aliphatic Uncharged Residues G, A, V, L, and I

[0584] Non-polar Uncharged Residues C, M, and P

[0585]

[0586] Aromatic Residues F, Y, and W

[0587] Table 3: Alternative Physical and Functional Classifications of Amino Acid Residues

[0588] Class Amino acid

[0589] Hydroxyl group containing residues S and T

[0590] Aliphatic residues I, L, V, and M

[0591] Cycloalkenyl-associated residues F, H, W, and Y

[0592] Hydrophobic residues A, C, F, G, H, I, L, M, R, T, V, W, and Y Negatively charged residues D and E

[0593] Polar residues C, D, E, H, K, N, Q, R, S, and T

[0594] Positively charged residues H, K, and R

[0595] Small residues A, C, D, G, N, P, S, T, and V

[0596] Very small residues A, G, and S

[0597] Residues involved in turn formation A, C, D, E, G, H, K, N, Q, R, S, P, and T

[0598]

[0599] Flexible residues Q, T, K, S, G, P, D, E, and R

[0600] Unless indicated to the contrary, an "amino acid" or "amino acid residue" as used herein preferably refers to one of the 22 natural amino acids, 20 of which are listed in Table 2 (and are encoded by theuniversal genetic code) and the remaining 2 of which are selenocysteine and pyrrolysine (these 2 amino acids are incorporated into proteins by unique synthesis mechanisms). These 22 amino acids are also called "proteinogenic amino acids" or "natural amino acids". The term "unnatural amino acid" as used herein refers to any amino acid which is not a natural amino acid (e.g., citrulline and homocysteine are examples of unnatural amino acids).

[0601] For the purposes of the present disclosure, "variants" of an amino acid sequence (peptide, protein or polypeptide) comprise amino acid insertion variants, amino acid addition variants, amino acid deletion variants and / or amino acid substitution variants. The term "variant" includes all mutants, splice variants, post-translationally modified variants, conformations, isoforms, allelic variants, species variants, and species homologs, in particular those which are naturally occurring. The term "variant" includes, in particular, fragments of an amino acid sequence.

[0602] Amino acid insertion variants comprise insertions of single or two or more amino acids in a particular amino acid sequence. In the case of amino acid sequence variants having an insertion, one or more amino acid residues are inserted into a particular site in an amino acid sequence, although random insertion with appropriate screening of the resulting product is also possible.

[0603] Amino acid addition variants comprise amino- and / or carboxy-terminal fusions of one or more amino acids, such as 1, 2, 3, 5, 10, 20, 30, 50, or more amino acids.

[0604] Amino acid deletion variants are characterized by the removal of one or more amino acids from the sequence, such as by removal of 1, 2, 3, 5, 10, 20, 30, 50, or more amino acids. The deletions may be in any position of the protein. Amino acid deletion variants that comprise the deletion at the N-terminal and / or C-terminal end of the protein are also called N-terminal and / or C-terminal truncation variants. Amino acid substitution variants are characterized by at least one residue in the sequence being removed and another residue being inserted in its place. Substitution of one amino acid for another may be classified as a conservative or non-conservative substitution. Preference is given to the modifications being in positions in the amino acid sequence which are not conserved between homologous proteins or peptides and / or to replacing amino acids with other ones having similar properties. Preferably, amino acid changes in peptide and protein variants are conservative amino acid changes, i.e., substitutions of similarly charged or uncharged amino acids. A conservative amino acid change involves substitution of one of a family of amino acids which are related in their side chains. In the context of the present disclosure, a "conservative substitution" is a substitution of one amino acid with another amino acid having similar structural and / or chemical characteristics, such substitution of one amino acid residue for another amino acid residue of the same class as defined in any of the two tables above: for example, leucine may be substituted with isoleucine as they are both aliphatic, branched hydrophobes. Similarly, aspartic acid may be substituted with glutamic acid since they are both small, negatively charged residues. Naturally occurring amino acids may also be generally divided into four families: acidic (aspartate, glutamate), basic (lysine, arginine, histidine), non-polar (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine,cysteine, serine, threonine, tyrosine) amino acids. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids. In one embodiment, conservative amino acid substitutions include substitutions within the following groups:

[0605] - glycine, alanine;

[0606] - valine, isoleucine, leucine;

[0607] - aspartic acid, glutamic acid;

[0608] - asparagine, glutamine;

[0609] - serine, threonine;

[0610] - lysine, arginine; and

[0611] - phenylalanine, tyrosine.

[0612] The term "amino acid corresponding to position..." and similar expressions as used herein refer to an amino acid position number in a human IgGl heavy chain. Corresponding amino acid positions in other immunoglobulins may be found by alignment with human IgGl. Thus, an amino acid or segment in one sequence that "corresponds to" an amino acid or segment in another sequence is one that aligns with the other amino acid or segment using a standard sequence alignment program such as ALIGN, ClustalW or similar, typically at default settings and has at least 50%, at least 80%, at least 90%, or at least 95% identity to a human IgGl heavy chain. It is considered well-known in the art how to align a sequence or segment in a sequence and thereby determine the corresponding position in a sequence to an amino acid position according to the present disclosure.

[0613] The term "antibody" (Ab) in the context of the present disclosure refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of either thereof, which has the ability to specifically bind to an antigen (in particular an epitope on an antigen) under typical physiological conditions, preferably with a half-life of significant periods of time, such as at least about 30 minutes, at least about 45 minutes, at least about one hour, at least about two hours, at least about four hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, about 48 hours or more, about 3, 4, 5, 6, 7 or more days, etc., or any other relevant functionally defined period (such as a time sufficient to induce, promote, enhance, and / or modulate a physiological response associated with antibody binding to the antigen and / or time sufficient for the antibody to recruit an effector activity). In particular, the term "antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. The term "antibody" includes monoclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, chimeric antibodies and combinations of any of the foregoing. Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (CH). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The variable regions and constant regions are also referred to herein as variable domains and constant domains, respectively. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each VHand VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The CDRs of a VH are termed HCDR1, HCDR2 and HCDR3 (or CDR-H1, CDR-H2 and CDR-H3), the CDRs of a VL are termed LCDR1, LCDR2 and LCDR3 (or CDR-L1, CDR-L2 and CDR-L3). The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of an antibody comprise the heavy chain constant region (CH) and the light chain constant region (CL), wherein CH can be further subdivided into constant domain CHI, a hinge region, and constant domains CH2 and CH3 (arranged from amino-terminus to carboxy-terminus in the following order: CHI, CH2, CH3). The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and components of the complement system such as Clq. Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoactive portions of intact immunoglobulins. Antibodies are typically tetramers of immunoglobulin molecules. Antibodies may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab and F(ab')2, as well as single chain antibodies and humanized antibodies.

[0614] The variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with an antigen. The terms "binding region" and "antigen-binding region" are used herein interchangeably and refer to the region which interacts with the antigen and comprises at least a single variable domain, such as a heavy chain variable (VH) region or both a VH region and a VL region. An antibody as used herein comprises not only monospecific antibodies, but also multispecific antibodies which comprise multiple, such as two or more, e.g., three or more, different antigen-binding regions.

[0615] As indicated above, the term antibody herein, unless otherwise stated or clearly contradicted by context, includes fragments of an antibody that are antigen-binding fragments, i.e., retain the ability to specifically bind to the antigen. It has been shown that the antigen-binding function of an antibody may be performed by fragments of a full-length antibody. Examples of antigen-binding fragments encompassed within the term "antibody" include (i) a Fab' or Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains, or a monovalent antibody as described in WO 2007 / 059782 (Genmab); (ii) F(ab’)2 fragments, bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting essentially of the VH and CHI domains; (iv) a Fv fragment consisting essentially of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment (Ward etal., Nature 341, 544-546 (1989)), which consists essentially of a VH domain and also called domain antibodies (Holt et al; Trends Biotechnol. 2003 Nov;21(11):484-90) or single domain antibodies; (vi) camelid or Nanobody molecules (Revets et al; Expert Opin Biol Ther. 2005 Jan;5(1):111-24); and (vii) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they may be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules(known as single chain antibodies or single chain Fv (scFv), see for instance Bird et al., Science 242, 423-426 (1988) and Huston etal., PNAS USA 85, 5879-5883 (1988)). Such single chain antibodies are encompassed within the term antibody unless otherwise noted or clearly indicated by context. Although such fragments are generally included within the meaning of antibody, they collectively and each independently are unique features of the present disclosure, exhibiting different biological properties and utility. These and other useful antibody fragments in the context of the present disclosure, as well as bispecific formats of such fragments, are discussed further herein. It also should be understood that the term antibody, unless specified otherwise, also includes polyclonal antibodies, monoclonal antibodies (mAbs), antibody-like polypeptides, such as chimeric antibodies and humanized antibodies, and antibody fragments retaining the ability to specifically bind to the antigen (antigen-binding fragments) provided by any known technique, such as enzymatic cleavage, peptide synthesis, and recombinant techniques.

[0616] A "single domain antibody" (sdAb) is an antibody composed of a single variable domain (e.g., heavy chain variable region) composed of antibody fragments. Typically, a single domain antibody, domain antibody or nanobody consists of 4 framework regions (FR1-FR4) and 3 complementarity determining regions (CDR1-CDR3). In some embodiments, the single domain antibody has the structure FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. These antibodies do not require light chain variable regions to bind antigens with high affinity and specificity. Examples of single domain antibodies include, but are not limited to, VHH fragments, and VNAR fragments. Compared with antibodies composed of heavy chain and light chain, single domain antibodies have high solubility, high stability to heat, pH, protease and other deforming agents, and only need single chain expression to facilitate large scale production.

[0617] A " VNAR" as used herein refers to a variable new Antigen receptor which is the smallest single domain antibody derived from the variable domain of shark immunoglobulin new antigen receptor (IgNAR) of cartilaginous fishes.

[0618] An antibody as generated can possess any isotype. As used herein, the term "isotype" refers to the immunoglobulin class (for instance IgG (such as IgGl, IgG2, IgG3, IgG4), IgD, IgA (such as IgAl, IgA2), IgE, IgM, or IgY) that is encoded by heavy chain constant region genes. When a particular isotype, e.g., IgGl, is mentioned herein, the term is not limited to a specific isotype sequence, e.g., a particular IgGl sequence, but is used to indicate that the antibody is closer in sequence to that isotype, e.g., IgGl, than to other isotypes. Thus, e.g., an IgGl antibody disclosed herein may be a sequence variant of a naturally occurring IgGl antibody, including variations in the constant regions.

[0619] IgGl antibodies can exist in multiple polymorphic variants termed allotypes (reviewed in Jefferis and Lefranc 2009. mAbs Vol 1 Issue 4 1-7) any of which are suitable for use in some of the embodiments herein. Common allotypic variants in human populations are those designated by the letters a, f, n, z or combinations thereof. In any of the embodiments herein, the antibody may comprise a heavy chain Fc region comprising a human IgG Fc region. In further embodiments, the human IgG Fc region comprises a human IgGl.The term "multispecific antibody" in the context of the present disclosure refers to an antibody having at least two different antigen-binding regions defined by different antibody sequences. In some embodiments, said different antigen-binding regions bind different epitopes on the same antigen. However, in preferred embodiments, said different antigen-binding regions bind different target antigens. In one embodiment, the multispecific antibody is a "bispecific antibody" or "bs". A multispecific antibody, such as a bispecific antibody, can be of any format, including any of the bispecific or multispecific antibody formats described herein below.

[0620] The prefixes BisGl and bsIgGl are used interchangeably herein for bispecific antibodies.

[0621] The term "full-length" when used in the context of an antibody indicates that the antibody is not a fragment, but contains all of the domains of the particular isotype normally found for that isotype in nature, e.g., the VH, CHI, CH2, CH3, hinge, VL and CL domains for an IgGl antibody.

[0622] The term "human antibody", as used herein, is intended to include antibodies having variable and framework regions derived from human germline immunoglobulin sequences and a human immunoglobulin constant domain. The human antibodies disclosed herein may include amino acid residues not encoded by human germline immunoglobulin sequences e.g., mutations, insertions or deletions introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another non-human species, such as a mouse, have been grafted onto human framework sequences.

[0623] The term "chimeric antibody" as used herein refers to an antibody wherein the variable region is derived from a non-human species {e.g., derived from rodents) and the constant region is derived from a different species, such as human. Chimeric antibodies may be generated by antibody engineering. " Antibody engineering" is a term used generically for different kinds of modifications of antibodies, and processes for antibody engineering are well-known for the skilled person. In particular, a chimeric antibody may be generated by using standard DNA techniques as described in Sambrook etal., 1989, Molecular Cloning: A laboratory Manual, New York: Cold Spring Harbor Laboratory Press, Ch. 15. Thus, the chimeric antibody may be a genetically or an enzymatically engineered recombinant antibody. It is within the knowledge of the skilled person to generate a chimeric antibody, and thus, generation of the chimeric antibody may be performed by other methods than those described herein. Chimeric monoclonal antibodies for therapeutic applications in humans are developed to reduce anticipated antibody immunogenicity of non-human antibodies, e.g., rodent antibodies. They may typically contain non-human {e.g., murine or rabbit) variable regions, which are specific for the antigen of interest, and human constant antibody heavy and light chain domains. The terms "variable region" or "variable domain" as used in the context of chimeric antibodies, refer to a region which comprises the CDRs and framework regions of both the heavy and light chains of an immunoglobulin, as described below. The term "humanized antibody" as used herein refers to a genetically engineered non-human antibody, which contains human antibody constant domains and non-human variable domains modified to containa high level of sequence homology to human variable domains. This can be achieved by grafting of the six non-human antibody complementarity-determining regions (CDRs), which together form the antigen binding site, onto a homologous human acceptor framework region (FR) (see WO 92 / 22653 and EP 0 629 240). In order to fully reconstitute the binding affinity and specificity of the parental antibody, the substitution of framework residues from the parental antibody ( / .e. the non-human antibody) into the human framework regions (back-mutations) may be required. Structural homology modeling may help to identify the amino acid residues in the framework regions that are important for the binding properties of the antibody. Thus, a humanized antibody may comprise non-human CDR sequences, primarily human framework regions optionally comprising one or more amino acid back-mutations to the non-human amino acid sequence, and fully human constant regions. Optionally, additional amino acid modifications, which are not necessarily back-mutations, may be applied to obtain a humanized antibody with preferred characteristics, such as affinity and biochemical properties.

[0624] As used herein, a protein which is "derived from" another protein, e.g., a parent protein, means that one or more amino acid sequences of the protein are identical or similar to one or more amino acid sequences in the other or parent protein. For example, in an antibody, binding arm, antigen-binding region, constant region, or the like which is derived from another or a parent antibody, binding arm, antigen-binding region, or constant region, one or more amino acid sequences are identical or similar to those of the other or parent antibody, binding arm, antigen-binding region, or constant region. Examples of such one or more amino acid sequences include, but are not limited to, those of the VH and VL CDRs and / or one or more or all of the framework regions, VH, VL, CL, hinge, or CH regions. For example, a humanized antibody can be described herein as "derived from" a non-human parent antibody, meaning that at least the VL and VH CDR sequences are identical or similar to the VH and VL CDR sequences of said non-human parent antibody. A chimeric antibody can be described herein as being "derived from" a non-human parent antibody, meaning that typically the VH and VL sequences may be identical or similar to those of the non-human parent antibody. Another example is a binding arm or an antigen-binding region which may be described herein as being "derived from" a particular parent antibody, meaning that said binding arm or antigen-binding region typically comprises identical or similar VH and / or VL CDRs, or VH and / or VL sequences to the binding arm or antigen-binding region of said parent antibody. As described elsewhere herein, however, amino acid modifications such as mutations can be made in the CDRs, constant regions or elsewhere in the antibody, binding arm, antigen-binding region or the like, to introduce desired characteristics. When used in the context of one or more sequences derived from a first or parent protein, a "similar" amino acid sequence preferably has a sequence identity of at least about 50%, such as at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 97%, 98% or 99%.

[0625] Non-human antibodies can be generated in a number of different species, such as mouse, rabbit, chicken, guinea pig, llama and goat.

[0626] Monoclonal antibodies can be produced by a variety of techniques, including conventional monoclonal antibody methodology, e.g., the standard somatic cell hybridization technique of Kohler and Milstein,Nature 256: 495 (1975). Other techniques for producing monoclonal antibodies can be employed, e.g., viral or oncogenic transformation of B-lymphocytes or phage display techniques using libraries of antibody genes, and such methods are well known to a person skilled in the art.

[0627] Hybridoma production in such non-human species is a very well established procedure. Immunization protocols and techniques for isolation of splenocytes of immunized animals / non-human species for fusion are known in the art. Fusion partners e.g., murine myeloma cells) and fusion procedures are also known.

[0628] When used herein, unless contradicted by context, the term " Fab-arm" or "arm" refers to one heavy chain-light chain pair and is used interchangeably with "half molecules" herein.

[0629] The term "binding arm comprising an antigen-binding region" means an antibody molecule or fragment that comprises an antigen-binding region. Thus, a binding arm can comprise, e.g., the six VH and VL CDR sequences, the VH and VL sequences, a Fab or Fab' fragment, or a Fab-arm.

[0630] When used herein, unless contradicted by context, the term " Fc region" refers to an antibody region consisting of the two Fc sequences of the heavy chains of an immunoglobulin, wherein said Fc sequences comprise at least a hinge region, a CH2 domain, and a CH3 domain. In one embodiment, the term " Fc region", as used herein, refers to a region comprising, in the direction from the N- to C-terminal end of the antibody, at least a hinge region, a CH2 region and a CH3 region. An Fc region of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system.

[0631] In the context of the present disclosure, the term "induce Fc-mediated effector function to a lesser extent" used in relation to an antibody, including a multispecific antibody, means that the antibody induces Fc-mediated effector functions, such function in particular being selected from the list of IgG Fc receptor (FcgammaR, FcyR) binding, Clq binding, ADCC or CDC, to a lesser extent compared to a human IgGl antibody comprising (i) the same CDR sequences, in particular comprising the same first and second antigen-binding regions, as said antibody and (ii) two heavy chains comprising human IgGl hinge, CH2 and CH3 regions.

[0632] Fc-mediated effector function may be measured by binding to FcyRs, binding to Clq, or induction of Fc-mediated cross-linking via FcyRs.

[0633] The term "hinge region" as used herein refers to the hinge region of an immunoglobulin heavy chain. Thus, for example, the hinge region of a human IgGl antibody corresponds to amino acids 216-230 according to the EU numbering as set forth in Kabat (Kabat, E. A. et al., Sequences of proteins of immunological interest. 5th Edition - US Department of Health and Human Services, NIH publication No.

[0634] 91-3242, pp 662,680,689 (1991). However, the hinge region may also be any of the other subtypes as described herein.The term " CHI region" or " CHI domain" as used herein refers to the CHI region of an immunoglobulin heavy chain. Thus, for example, the CHI region of a human IgGl antibody corresponds to amino acids 118-215 according to the EU numbering as set forth in Kabat ibid). However, the CHI region may also be any of the other subtypes as described herein.

[0635] The term " CH2 region" or " CH2 domain" as used herein refers to the CH2 region of an immunoglobulin heavy chain. Thus, for example, the CH2 region of a human IgGl antibody corresponds to amino acids 231-340 according to the EU numbering as set forth in Kabat (ibid). However, the CH2 region may also be any of the other subtypes as described herein.

[0636] The term " CH3 region" or " CH3 domain" as used herein refers to the CH3 region of an immunoglobulin heavy chain. Thus, for example, the CH3 region of a human IgGl antibody corresponds to amino acids 341-447 according to the EU numbering as set forth in Kabat (ibid). However, the CH3 region may also be any of the other subtypes as described herein.

[0637] The term "monovalent antibody" means in the context of the present disclosure that an antibody molecule is capable of binding a single molecule of the antigen, and thus is not capable of antigen crosslinking.

[0638] A " PD-1 antibody" or "anti-PD-1 antibody" is an antibody as described above, which is directed against the antigen PD-1 and which preferably binds specifically to the antigen PD-1.

[0639] A " PD-L1 antibody" or "anti-PD-Ll antibody" is an antibody as described above, which is directed against the antigen PD-L1 and which preferably binds specifically to the antigen PD-L1.

[0640] A " VEGF antibody" or "anti-VEGF antibody" is an antibody as described above, which is directed against the antigen VEGF and which preferably binds specifically to the antigen VEGF.

[0641] A " VEGFR antibody" or "anti-VEGFR antibody" is an antibody as described above, which is directed against the antigen VEGFR and which preferably binds specifically to the antigen VEGFR.

[0642] An " EpCAM antibody" or "anti-EpCAM antibody" is an antibody as described above, which binds specifically to the antigen EpCAM.

[0643] A "4-1BB antibody" or "anti-4-lBB antibody" is an antibody as described above, which binds specifically to the antigen 4-1BB (CD137).

[0644] An " PD-1 / PD-LlxVEGF / VEGFR antibody" or "anti-PD-1 / PD-LlxVEGF / VEGFR antibody" is a bispecific antibody, which comprises two different antigen-binding regions, one of which binds specifically to PD-1 or PD-L1 or both and one of which binds specifically VEGF or VEGFR or both.

[0645] An " EpCAMx4-lBB antibody" or "anti-EpCAMx4-lBB antibody" is a bispecific antibody, which comprises two different antigen-binding regions, one of which binds specifically to the antigen EpCAM and one of which binds specifically to the antigen 4-1BB.The term "biosimilar" (e.g., of an approved reference product / biological drug) as used herein refers to a biologic product that is similar to the reference product based on data from (a) analytical studies demonstrating that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and / or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is approved and intended to be used and for which approval is sought (e.g., that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product). In some embodiments, the biosimilar biological product and reference product utilizes the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product. In some embodiments, the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product. In some embodiments, the route of administration, the dosage form, and / or the strength of the biological product are the same as those of the reference product. A biosimilar can be, e.g., a presently known antibody having the same primary amino acid sequence as a marketed antibody, but may be made in different cell types or by different production, purification, or formulation methods.

[0646] As used herein, the terms "binding" or "capable of binding" in the context of the binding of an antibody to a predetermined antigen or epitope typically is a binding with an affinity corresponding to a KD of about 10-7M or less, such as about 10-8M or less, such as about 10-9M or less, about 10-10M or less, or about 10-11M or even less, when determined, for instance, using Bio-Layer Interferometry (BLI) or using surface plasmon resonance (SPR) technology in a BIAcore 3000 instrument using the antigen as the ligand and the antibody as the analyte. The antibody binds to the predetermined antigen with an affinity corresponding to a KD that is at least ten-fold lower, such as at least 100-fold lower, for instance at least 1,000-fold lower, such as at least 10,000-fold lower, for instance at least 100,000-fold lower than its KD for binding to a non-specific antigen e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen. The amount with which the affinity is higher is dependent on the KD of the antibody, so that when the KD of the antibody is very low (that is, the antibody is highly specific), then the degree to which the affinity for the antigen is lower than the affinity for a non-specific antigen may be at least 10,000-fold.

[0647] The term "kd" (sec-1), as used herein, refers to the dissociation rate constant of a particular antibodyantigen interaction. Said value is also referred to as the koff value.

[0648] The term " KD" (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction.Two antibodies have the "same specificity" if they bind to the same antigen and to the same epitope. Whether an antibody to be tested recognizes the same epitope as a certain antigen-binding antibody, i.e., the antibodies bind to the same epitope, may be tested by different methods well known to a person skilled in the art.

[0649] The competition between the antibodies can be detected by a cross-blocking assay. For example, a competitive ELISA assay may be used as a cross-blocking assay. E.g., target antigen may be coated on the wells of a microtiter plate and antigen-binding antibody and candidate competing test antibody may be added. The amount of the antigen-binding antibody bound to the antigen in the well indirectly correlates with the binding ability of the candidate competing test antibody that competes therewith for binding to the same epitope. Specifically, the larger the affinity of the candidate competing test antibody is for the same epitope, the smaller the amount of the antigen-binding antibody bound to the antigen-coated well. The amount of the antigen-binding antibody bound to the well can be measured by labeling the antibody with detectable or measurable labeling substances.

[0650] An antibody competing for binding to an antigen with another antibody, e.g., an antibody comprising heavy and light chain variable regions as described herein, or an antibody having the specificity for an antigen of another antibody, e.g., an antibody comprising heavy and light chain variable regions as described herein, may be an antibody comprising variants of said heavy and / or light chain variable regions as described herein, e.g. modifications in the CDRs and / or a certain degree of identity as described herein.

[0651] An "isolated multispecific antibody" as used herein is intended to refer to a multispecific antibody which is substantially free of other antibodies having different antigenic specificities. For instance, an isolated bispecific antibody that specifically binds to EpCAM and 4-1BB is substantially free of monospecific antibodies that specifically bind to EpCAM or 4-1BB). Similarly, an isolated bispecific antibody that specifically binds to PD-1 or PD-L1 or both and VEGF or VEGFR or both is substantially free of monospecific antibodies that specifically bind to PD-1, PD-L1, VEGF or VEGFR.

[0652] When used herein the term "heterodimeric interaction between the first and second CH3 regions" refers to the interaction between the first CH3 region and the second CH3 region in a first-CH3 / second-CH3 heterodimeric antibody.

[0653] When used herein the term "homodimeric interactions of the first and second CH3 regions" refers to the interaction between a first CH3 region and another first CH3 region in a first-CH3 / first-CH3 homodimeric antibody and the interaction between a second CH3 region and another second CH3 region in a second-CH3 / second-CH3 homodimeric antibody.

[0654] When used herein the term "homodimeric antibody" refers to an antibody comprising two first Fab-arms or half-molecules, wherein the amino acid sequence of said Fab-arms or half-molecules is the same. When used herein the term "heterodimeric antibody" refers to an antibody comprising a first and a second Fab-arm or half-molecule, wherein the amino acid sequence of said first and second Fab-armsor half-molecules are different. In particular, the CH3 region, or the antigen-binding region, or the CH3 region and the antigen-binding region of said first and second Fab-arms / half-molecules are different. The term "reducing conditions" or "reducing environment" refers to a condition or an environment in which a substrate, such as a cysteine residue in the hinge region of an antibody, is more likely to become reduced than oxidized.

[0655] An antibody competing for binding to an antigen with another antibody, e.g., an antibody comprising heavy and light chain variable regions as described herein, or an antibody having the specificity for an antigen of another antibody, e.g., an antibody comprising heavy and light chain variable regions as described herein, may be an antibody comprising variants of said heavy and / or light chain variable regions as described herein, e.g. modifications in the CDRs and / or a certain degree of identity as described herein.

[0656] A binding region as defined herein (such as an antibody or a fragment thereof as defined herein) "antagonizes the PD-1 / PD-L1 interaction" means that the binding region is antagonistic towards the PD-1 / PD-L1 signaling pathway. In particular, such binding region which antagonizes the PD-1 / PD-L1 interaction totally or partially inhibits, reduces, interferes with or negatively modulates the PD-1 / PD-L1 signaling pathway by binding to PD-1, PD-L1, or both. Preferably, the binding region which antagonizes the PD-1 / PD-L1 interaction mediates its antagonistic activity in a manner that totally inhibits ( / .e., blocks) or partially reduces the binding of PD-L1 to PD-1.

[0657] A binding region as defined herein (such as an antibody or a fragment thereof as defined herein) "antagonizes the VEGF / VEGFR interaction" means that the binding region is antagonistic towards the VEGF / VEGFR signaling pathway. In particular, such binding region which antagonizes the VEGF / VEGFR interaction totally or partially inhibits, reduces, interferes with or negatively modulates the VEGF / VEGFR signaling pathway by binding to VEGF, VEGFR, or both. Preferably, the binding region which antagonizes the VEGF / VEGFR interaction mediates its antagonistic activity in a manner that totally inhibits ( / .e., blocks) or partially reduces the binding of VEGF to VEGFR.

[0658] A binding region as defined herein (such as an antibody or a fragment thereof as defined herein) "agonizes 4-1BB activity " means that the binding region activates the 4-1BB signaling pathway. In particular, such binding region which agonizes 4-1BB totally or partially activates or increases or positively modulates the 4-1BB signaling pathway by binding to 4-1BB.

[0659] The term "monoclonal antibody" as used herein refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0660] The present disclosure also describes antibodies, such as monoclonal antibodies, comprising functional variants of the VL regions, VH regions, or one or more CDRs of the antibodies of the examples. A functional variant of a VL, VH, or CDR used in the context of a antibody still allows the antigen-binding region of the bispecific antibody to retain at least a substantial proportion (at least about 50%, 60%,70%, 80%, 90%, 95% or more) of the affinity and / or the specificity / selectivity of the parent antibody and in some cases such an antibody may be associated with greater affinity, selectivity and / or specificity than the parent antibody.

[0661] Such functional variants typically retain significant sequence identity to the parent antibody. The percent identity between two sequences is a function of the number of identical positions shared by the sequences ( / .e., % homology = # of identical positions / total # of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The percent identity between two nucleotide or amino acid sequences may e.g., be determined using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci 4, 11-17 (1988) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences may be determined using the Needleman and Wunsch, J. Mol. Biol. 48, 444-453 (1970) algorithm.

[0662] In the context of the present disclosure, unless otherwise indicated, the following notations are used to describe a mutation: i) substitution of an amino acid in a given position is written as, e.g., L234A (with the numbering according to the EU-index) which means a substitution of a leucine in position 234 of the protein with an alanine; and ii) for specific variants the specific three or one letter codes are used, including the codes Xaa and X to indicate any amino acid residue. Thus, the substitution of leucine with alanine in position 234 is designated as: L234A (with the numbering according to the EU-index), and the substitution of leucine with any amino acid residue in position 234 is designated as L234X. In case of deletion of leucine in position 234 it is indicated by L234*. As noted, amino acids are numbered according to the EU numbering (EU-index) as set forth in Kabat (Kabat, E. A.; National Institutes of Health (U. S.) Office of the Director. Sequences of Proteins of Immunological Interest, 5th ed.; DIANE Publishing: Collingdale, PA, USA, 1991).

[0663] Exemplary variants include those which differ from the VH and / or VL and / or CDRs of the parent sequences mainly by conservative substitutions; for example, 12, such as 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 of the substitutions in the variant are conservative amino acid residue replacements.

[0664] In the context of the present disclosure, conservative substitutions may be defined by substitutions within the classes of amino acids as defined in Tables 2 and 3.

[0665] As used herein, "immune checkpoint" refers to regulators of the immune system, and, in particular, costimulatory and inhibitory signals that regulate the amplitude and quality of T cell receptor recognition of an antigen. In certain embodiments, the immune checkpoint is an inhibitory signal. In certain embodiments, the inhibitory signal is the interaction between PD-1 and PD-L1 and / or PD-L2. The terms "checkpoint inhibitor" (CPI) and "immune checkpoint (ICP) inhibitor" are used herein synonymously. The terms refer to molecules, such as binding agents, which totally or partially reduce, inhibit, interfere with or negatively modulate one or more checkpoint proteins or that totally or partially reduce, inhibit, interfere with or negatively modulate expression of one or more checkpoint proteins, like molecules,such as binding agents, which inhibit an immune checkpoint, in particular, which inhibit the inhibitory signal of an immune checkpoint. In one embodiment, the immune checkpoint inhibitor binds to one or more checkpoint proteins. In one embodiment, the immune checkpoint inhibitor binds to one or more molecules regulating checkpoint proteins. In one embodiment, the immune checkpoint inhibitor binds to precursors of one or more checkpoint proteins e.g., on DNA- or RNA-level. Any agent that functions as a checkpoint inhibitor according to the present disclosure can be used. The term "partially" as used herein means at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% in the level, e.g., in the level of inhibition of a checkpoint protein.

[0666] In one embodiment, the checkpoint inhibitor can be any compound, such as any binding agent, which inhibits the inhibitory signal of an immune checkpoint. In one embodiment, the inhibitory signal is the interaction between PD-1 and PD-L1 and / or PD-L2 (such a checkpoint inhibitor which inhibits the interaction between PD-1 and PD-L1 and / or PD-L2 is also called a PD-1 / PD-L1 checkpoint inhibitor herein). In one embodiment, the checkpoint inhibitor is at least one selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and PD-L2 inhibitors. In one embodiment, the checkpoint inhibitor may be a blocking antibody, such as a PD-1 blocking antibody, a PD-L1 blocking antibody, or a PD-L2 blocking antibody. Examples of a PD-1 blocking antibody include pembrolizumab, nivolumab, cemiplimab, and spartalizumab. Examples of a PD-L1 blocking antibody include atezolizumab, durvalumab, and avelumab.

[0667] In one embodiment, the immune checkpoint inhibitor suitable for use in the aspects of the present disclosure is an antibody which targets PD-1 or PD-L1. In a preferred embodiment, the immune checkpoint inhibitor suitable for use in the aspects of the present disclosure is pembrolizumab.

[0668] The " Programmed Death-1 (PD-1)" receptor refers to an immuno-inhibitory receptor belonging to the CD28 family. PD-1 (also known as CD279) is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). The term " PD-1" as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. " Programmed Death Ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that downregulates T cell activation and cytokine secretion upon binding to PD-1. The term " PD-L1" as used herein includes human PD-L1 (hPD-Ll), variants, isoforms, and species homologs of hPD-Ll, such as macaque (cynomolgus monkey), African elephant, wild boar and mouse PD-L1 (cf., e.g., Gen bank accession no. NP_054862.1, XP_005581836, XP_003413533, XP_005665023 and NP_068693, respectively), and analogs having at least one common epitope with hPD-Ll. The term " PD-L2" as used herein includes human PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, and analogs having at least one common epitope with hPD-L2. The ligands of PD-1 (PD-L1 and PD-L2) are expressed on the surface of antigen-presenting cells, such as dendritic cells or macrophages, and other immune cells. Binding of PD-1 to PD-L1 or PD-L2 results in downregulation of T cell activation. Cancer cells expressing PD-L1 and / or PD-L2 are able to switch off T cells expressing PD-1 what results insuppression of the anticancer immune response. The interaction between PD-1 and its ligands results in a decrease in tumor infiltrating lymphocytes, a decrease in T cell receptor mediated proliferation, and immune evasion by the cancerous cells. Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well.

[0669] Many of the immune checkpoints are regulated by interactions between specific receptor and ligand pairs, such as those described above. Thus, immune checkpoint proteins mediate immune checkpoint signaling. For example, checkpoint proteins directly or indirectly regulate T cell activation, T cell proliferation and / or T cell function. Cancer cells often exploit these checkpoint pathways to protect themselves from being attacked by the immune system. Hence, the function of checkpoint proteins is typically the regulation ofT cell activation, T cell proliferation and / orT cell function. Immune checkpoint proteins thus regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Many of the immune checkpoint proteins belong to the B7: CD28 family or to the tumor necrosis factor receptor (TNFR) super family and, by binding to specific ligands, activate signaling molecules that are recruited to the cytoplasmic domain (Suzuki et al., 2016, Jap J Clin Onc, 46:191-203).

[0670] The term " VEGF" as used herein refers to vascular endothelial growth factor (VEGF) which is a member of the platelet-derived growth factor family of cystine-knot growth factors, i.e., a group of signal proteins involved in vasculogenesis and angiogenesis. Upon binding to tyrosine kinase receptors (VEGF receptors (VEGFRs)), the VEGFR dimerizes and becomes activated through transphosphorylation. Overexpression of VEGF can cause vascular diseases. Drugs which target VEGF (e.g., aflibercept, bevacizumab, ranibizumab, and pegaptanib) can inhibit VEGF and, thus, slow such diseases. In one embodiment, VEGF is human VEGF, in particular human VEGF comprising the amino acid sequence of SEQ ID NO: 176. In some embodiments, VEGF is human VEGF-A, in particular human VEGF-A comprising the amino acid sequence of SEQ ID NO: 177.

[0671] The term " VEGFR" as used herein refers to a VEGF receptor, which is tyrosine kinase receptor. Upon binding of a VEGF to the VEGFR, the VEGFR dimerizes and becomes activated through transphosphorylation.

[0672] The term " EpCAM" as used herein, refers to epithelial cell adhesion molecule, also referred to as DIAR5, EGP-2, EGP314, EGP40, ESA, HNPCC8, KS1 / 4, KSA, M4S1, MIC18, MK-1, TACSTD1, TROP1, BerEp4, MOC-31, Ber-Ep4. EpCAM is believed to have many different roles, and appears to play a role in cell adhesion and cancer. In one embodiment, EpCAM is human EpCAM, having UniProt accession number P16422. The sequence of human EpCAM is also shown in SEQ ID NO: 59. Amino acids 1-23 of SEQ ID NO: 59 correspond to the signal peptide of human EpCAM; while amino acids 24-265 of SEQ ID NO: 59 correspond to the extracellular domain of human EpCAM; and the remainder of the protein, i.e., from amino acids 266-288 and 289-314 of SEQ ID NO: 59 are transmembrane and cytoplasmic domain, respectively.The term "4-1BB" as used herein, refers interchangeably to 4-1BB or CD137, also referred to as tumor necrosis factor receptor superfamily member 9 (TNFRSF9), which is the receptor for the ligand TNFSF9 / 4-1BBL. 4-1BB is believed to be involved in T-cell activation. Other synonyms for 4-1BB include, but are not limited to, CD137 receptor, CDwl37, T-cell antigen 4-1BB homolog and T-cell antigen ILA. In one embodiment, 4-1BB is human 4-1BB, having UniProt accession number Q07011. The sequence of human 4-1BB is also shown in SEQ ID NO: 37. Amino acids 1-23 of SEQ ID NO: 37 correspond to the signal peptide of human 4-1BB; while amino acids 24-186 of SEQ ID NO: 37 correspond to the extracellular domain of human 4-1BB; and the remainder of the protein, i.e., from amino acids 187-213 and 214-255 of SEQ ID NO: 37 are transmembrane and cytoplasmic domain, respectively.

[0673] " Treatment cycle" is herein defined as the time period, within the effects of separate dosages of the therapeutic agent (e.g., the anti-PD-l / PD-LlxVEGF / VEGFR binding agent or the anti-EpCAMx4-lBB binding agent) cease to exist due to its pharmacodynamics, or in other words the time period after the subject's body is essentially cleared from the administrated therapeutic agent. Multiple small doses in a small time window, e.g. within 2-24 few hours, such as 2-12 hours or on the same day, might be equal to a larger single dose.

[0674] In the present context, the term "treatment", "treating" or "therapeutic intervention" relates to the management and care of a subject for the purpose of combating a condition such as a disease or disorder. The term is intended to include the full spectrum of treatments for a given condition from which the subject is suffering, such as administration of the therapeutically effective compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and / or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of an individual for the purpose of combating the disease, condition or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. In one embodiment, "treatment" refers to the administration of an effective amount of a therapeutically active agent, such as of an anti-PD-l / PD-LlxVEGF / VEGFR binding agent and / or of an anti-EpCAMx4-lBB binding agent as disclosed herein, with the purpose of easing, ameliorating, arresting or eradicating (curing) symptoms or disease states.

[0675] The resistance to, failure to respond to and / or relapse from treatment with a therapeutic agent e.g., the anti-PD-l / PD-LlxVEGF / VEGFR binding agent or the anti-EpCAMx4-lBB binding agent) of the present disclosure may be determined according to the Response Evaluation Criteria in Solid Tumors; version 1.1 (RECIST Criteria vl.l). The RECIST Criteria are set forth in the table below (LD: longest dimension). Table 4: Definition of Response (RECIST Criteria vl.l)

[0676] Category Criteria

[0677] Based on target Complete Response Disappearance of all target lesions. Any pathological lymph lesions (CR) nodes must have reduction in short axis to < 10 mm.

[0678] Partial Response > 30% decrease in the sum of the LD of target lesions, taking

[0679]

[0680] (PR) as reference the baseline sum LD.Category Criteria

[0681] Stable Disease Neither sufficient shrinkage to qualify for PR nor sufficient (SD) increase to qualify for PD, taking as reference the smallest sum of LDs since the treatment started.

[0682] Progressive Disease > 20% increase in the sum of the LDs of target lesions, taking (PD) as reference the smallest sum of the LDs recorded since the treatment started or the appearance of one or more new lesions.

[0683] Based on nonCR Disappearance of all non-target lesions and normalization of target lesions tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).

[0684] SD Persistence of one or more non-target lesion(s) or / and maintenance of tumor marker level above the normal limits. PD Appearance of one or more new lesions and / or unequivocal

[0685]

[0686] progression of existing non-target lesions.

[0687] The "best overall response" is the best response recorded from the start of the treatment until disease progression / recurrence (the smallest measurements recorded since the treatment started will be used as the reference for PD). Subjects with CR or PR are considered to be objective response. Subjects with CR, PR or SD are considered to be in disease control. Subjects with NE are counted as non-responders. The best overall response is the best response recorded from the start of the treatment until disease progression / recurrence (the smallest measurements recorded since the treatment started will be used as the reference for PD). Subjects with CR, PR or SD are considered to be in disease control. Subjects with NE are counted as non-responders.

[0688] The objective response rate (ORR) is the percentage of all subjects in a study or treatment group who have either a partial or complete response to the treatment. The ORR can be calculated by adding the numbers of subjects having CR and the numbers of subjects having PR and dividing the resulting sum by the total number of subjects in the treatment group. The ORRevai, i.e., the ORR of all evaluable subjects in a study or treatment group, is the percentage of all evaluable subjects in a study or treatment group who have either a partial or complete response to the treatment.

[0689] The disease control rate (DCR) is the percentage of all subjects in a study or treatment group who have either a complete response, a partial response, or a stable disease to the treatment (CR, PR or SD). The DCR can be calculated by adding the numbers of subjects having CR, the numbers of subjects having PR, and the numbers of subjects having SD and dividing the resulting sum by the total number of subjects in the treatment group. The DCRevai, i.e., the DCR of all evaluable subjects in a study or treatment group, is the percentage of all evaluable subjects in a study or treatment group who have either a complete response, a partial response, or a stable disease to the treatment (CR, PR or SD). " Duration of response (DOR)" only applies to subjects whose confirmed best overall response is CR or PR and is defined as the time from the first documentation of objective tumor response (CR or PR) to the date of first PD or death due to underlying cancer." Progression-free survival (PFS)" is defined as the number of days from Day 1 in Cycle 1 to the first documented progression or death due to any cause.

[0690] " Overall survival (OS)" is defined as the number of days from Day 1 in Cycle 1 to death due to any cause. If a subject is not known to have died, then OS will be censored at the latest date the subject was known to be alive (on or before the cut-off date).

[0691] In the context of the present disclosure, the term "treatment regimen" refers to a structured treatment plan designed to improve and maintain health.

[0692] The term "effective amount" or "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount of a therapeutic agent, such as an antibody, may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agent are outweighed by the therapeutically beneficial effects. In the case that a reaction in a patient is insufficient with an initial dose, higher doses (or effectively higher doses achieved by a different, more localized route of administration) may be used. In case that unwanted side effects occur in a patient with a dose, lower doses (or effectively lower doses achieved by a different, more localized route of administration) may be used.

[0693] As used herein, the term "cancer disease" or "cancer" refers to or describes the physiological condition in an individual that is typically characterized by unregulated cell growth and typically a disease characterized by aberrantly regulated cellular growth, proliferation, differentiation, adhesion, and / or migration. By "cancer cell" is meant an abnormal cell that grows by a rapid, uncontrolled cellular proliferation and continues to grow after the stimuli that initiated the new growth cease.

[0694] The term "cancer" according to the present disclosure also comprises cancer metastases. By "metastasis" is meant the spread of cancer cells from its original site to another part of the body. The formation of metastasis is a very complex process and depends on detachment of malignant cells from the primary tumor, invasion of the extracellular matrix, penetration of the endothelial basement membranes to enter the body cavity and vessels, and then, after being transported by the blood, infiltration of target organs. Finally, the growth of a new tumor, i.e. a secondary tumor or metastatic tumor, at the target site depends on angiogenesis. Tumor metastasis often occurs even after the removal of the primary tumor because tumor cells or components may remain and develop metastatic potential. In one embodiment, the term "metastasis" according to the present disclosure relates to "distant metastasis" which relates to a metastasis which is remote from the primary tumor and the regional lymph node system.

[0695] Terms such as "reduce", "inhibit", "interfere", and "negatively modulate" as used herein means an overall decrease or the ability to cause an overall decrease, for example, of about 5% or greater, about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% orgreater, about 40% or greater, about 50% or greater, or about 75% or greater, in the level. The term "inhibit" or similar phrases includes a complete or essentially complete inhibition, i.e. a reduction to zero or essentially to zero.

[0696] Terms such as "increase" or "enhance" in one embodiment relate to an increase or enhancement by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 80%, or at least about 100%.

[0697] " Physiological pH" as used herein refers to a pH of about 7.5.

[0698] The term "ionic strength" refers to the mathematical relationship between the number of different kinds of ionic species in a particular solution and their respective charges. Thus, ionic strength I is represented mathematically by the formula

[0699]

[0700] ,=r X iz‘ 'c‘

[0701] in which c is the molar concentration of a particular ionic species and z the absolute value of its charge. The sum Z is taken over all the different kinds of ions (i) in solution. According to the disclosure, the term "ionic strength" in one embodiment relates to the presence of monovalent ions. Regarding the presence of divalent ions, in particular divalent cations, their concentration or effective concentration (presence of free ions) due to the presence of chelating agents is in one embodiment sufficiently low so as to prevent degradation of RNA. In one embodiment, the concentration or effective concentration of divalent ions is below the catalytic level for hydrolysis of the phosphodiester bonds between RNA nucleotides. In one embodiment, the concentration of free divalent ions is 20 pM or less. In one embodiment, there are no or essentially no free divalent ions.

[0702] As used in the present disclosure, "% by weight" refers to weight percent, which is a unit of concentration measuring the amount of a substance in grams (g) expressed as a percent of the total weight of the total composition in grams (g).

[0703] The term "freezing" relates to the solidification of a liquid, usually with the removal of heat.

[0704] The term "lyophilizing" or "lyophilization" refers to the freeze-drying of a substance by freezing it and then reducing the surrounding pressure (e.g., below 15 Pa, such as below 10 Pa, below 5 Pa, or 1 Pa or less) to allow the frozen medium in the substance to sublimate directly from the solid phase to the gas phase. Thus, the terms "lyophilizing" and "freeze-drying" are used herein interchangeably.

[0705] The term "spray-drying" refers to spray-drying a substance by mixing (heated) gas with a fluid that is atomized (sprayed) within a vessel (spray dryer), where the solvent from the formed droplets evaporates, leading to a dry powder.

[0706] The term "cryoprotectant" relates to a substance that is added to a formulation in order to protect the active ingredients during the freezing stages.The term "lyoprotectant" relates to a substance that is added to a formulation in order to protect the active ingredients during the drying stages.

[0707] The term "reconstitute" relates to adding a solvent such as water to a dried product to return it to a liquid state such as its original liquid state.

[0708] The term "recombinant" in the context of the present disclosure means "made through genetic engineering". In one embodiment, a "recombinant object" in the context of the present disclosure is not occurring naturally.

[0709] The term "naturally occurring" as used herein refers to the fact that an object can be found in nature. For example, a peptide or nucleic acid that is present in an organism (including viruses) and can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally occurring. The term "found in nature" means "present in nature" and includes known objects as well as objects that have not yet been discovered and / or isolated from nature, but that may be discovered and / or isolated in the future from a natural source.

[0710] According to the present disclosure, the term "peptide" comprises oligo- and polypeptides and refers to substances which comprise about two or more, about 3 or more, about 4 or more, about 6 or more, about 8 or more, about 10 or more, about 13 or more, about 16 or more, about 20 or more, and up to about 50, about 100 or about 150, consecutive amino acids linked to one another via peptide bonds. The term "protein" refers to large peptides, in particular peptides having at least about 151 amino acids, but the terms "peptide" and "protein" are used herein usually as synonyms. A preferred example of a peptide is an antigen, such as tumor-associated antigen.

[0711] The term "portion" refers to a fraction. With respect to a particular structure such as an amino acid sequence or protein the term "portion" thereof may designate a continuous or a discontinuous fraction of said structure.

[0712] The terms "part" and "fragment" are used interchangeably herein and refer to a continuous element. For example, a part of a structure such as an amino acid sequence or protein refers to a continuous element of said structure. When used in context of a composition, the term "part" means a portion of the composition. For example, a part of a composition may any portion from 0.1% to 99.9% (such as 0.1%, 0.5%, 1%, 5%, 10%, 50%, 90%, or 99%) of said composition.

[0713] " Fragment", with reference to an amino acid sequence (peptide or protein), relates to a part of an amino acid sequence, i.e. a sequence which represents the amino acid sequence shortened at the N-terminus and / or C-terminus. A fragment shortened at the C-terminus (N-terminal fragment) is obtainable, e.g., by translation of a truncated open reading frame that lacks the 3'-end of the open reading frame. A fragment shortened at the N-terminus (C-terminal fragment) is obtainable, e.g., by translation of a truncated open reading frame that lacks the 5'-end of the open reading frame, as long as the truncated open reading frame comprises a start codon that serves to initiate translation. A fragment of an amino acid sequence comprises, e.g., at least 50 %, at least 60 %, at least 70 %, at least 80%, at least 90%of the amino acid residues from an amino acid sequence. A fragment of an amino acid sequence preferably comprises at least 6, in particular at least 8, at least 12, at least 15, at least 20, at least 30, at least 50, or at least 100 consecutive amino acids from an amino acid sequence.

[0714] According to the present disclosure, a part or fragment of a peptide or protein preferably has at least one functional property of the peptide or protein from which it has been derived. Such functional properties comprise a pharmacological activity, the interaction with other peptides or proteins, an enzymatic activity, the interaction with antibodies, and the selective binding of nucleic acids. E.g., a pharmacological active fragment of a peptide or protein has at least one of the pharmacological activities of the peptide or protein from which the fragment has been derived. A part or fragment of a peptide or protein preferably comprises a sequence of at least 6, in particular at least 8, at least 10, at least 12, at least 15, at least 20, at least 30 or at least 50, consecutive amino acids of the peptide or protein. A part or fragment of a peptide or protein preferably comprises a sequence of up to 8, in particular up to 10, up to 12, up to 15, up to 20, up to 30 or up to 55, consecutive amino acids of the peptide or protein. By "variant", with reference to an amino acid sequence (peptide or protein), herein is meant an amino acid sequence that differs from a parent amino acid sequence by virtue of at least one amino acid modification. The parent amino acid sequence may be a naturally occurring or wild type (WT) amino acid sequence, or may be a modified version of a wild type amino acid sequence. Preferably, the variant amino acid sequence has at least one amino acid modification compared to the parent amino acid sequence, e.g., from 1 to about 20 amino acid modifications, and preferably from 1 to about 10 or from 1 to about 5 (such a 1, 2, 3, 4, or 5) amino acid modifications compared to the parent.

[0715] By "wild type" or " WT" or "native" herein is meant an amino acid sequence that is found in nature, including allelic variations. A wild type amino acid sequence, peptide or protein has an amino acid sequence that has not been intentionally modified.

[0716] Preferably the degree of similarity, preferably identity between a given amino acid sequence and an amino acid sequence which is a variant of said given amino acid sequence will be at least about 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. The degree of similarity or identity is given preferably for an amino acid region which is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% of the entire length of the reference amino acid sequence. For example, if the reference amino acid sequence consists of 200 amino acids, the degree of similarity or identity is given preferably for at least about 20, at least about 40, at least about 60, at least about 80, at least about 100, at least about 120, at least about 140, at least about 160, at least about 180, or about 200 amino acids, in some embodiments continuous amino acids. In some embodiments, the degree of similarity or identity is given for the entire length of the reference amino acid sequence. The alignment for determining sequence similarity, preferably sequence identity can be done with art known tools, preferably usingthe best sequence alignment, for example, using Align, using standard settings, preferably EMBOSS:: needle, Matrix: Blosum62, Gap Open 10.0, Gap Extend 0.5.

[0717] The disclosure describes nucleic acid sequences and amino acid sequences having a certain degree of similarity or identity to a given nucleic acid sequence or amino acid sequence, respectively (a reference sequence). " Sequence similarity" indicates the percentage of amino acids that either are identical or that represent conservative amino acid substitutions. " Sequence identity" between two amino acid sequences indicates the percentage of amino acids that are identical between the sequences. " Sequence identity" between two nucleic acid sequences indicates the percentage of nucleotides that are identical between the sequences.

[0718] The terms "% identical" and "% identity" or similar terms are intended to refer, in particular, to the percentage of nucleotides or amino acids which are identical in an optimal alignment between the sequences to be compared. Said percentage is purely statistical, and the differences between the two sequences may be but are not necessarily randomly distributed over the entire length of the sequences to be compared. Comparisons of two sequences are usually carried out by comparing the sequences, after optimal alignment, with respect to a segment or "window of comparison", in order to identify local regions of corresponding sequences. The optimal alignment for a comparison may be carried out manually or with the aid of the local homology algorithm by Smith and Waterman, 1981, Ads App. Math.

[0719] 2, 482, with the aid of the local homology algorithm by Neddleman and Wunsch, 1970, J. Mol. Biol. 48, 443, with the aid of the similarity search algorithm by Pearson and Lipman, 1988, Proc. Natl Acad. Sci. USA 88, 2444, or with the aid of computer programs using said algorithms (GAP, BESTFIT, FASTA, BLAST P, BLAST N and TFASTA in Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, Wis.). In some embodiments, percent identity of two sequences is determined using the BLASTN or BLASTP algorithm, as available on the United States National Center for Biotechnology Information (NCBI) website (e.g., at blast.ncbi.nlm.nih.gov / Blast.cgi). In some embodiments, the algorithm parameters used for BLASTN algorithm on the NCBI website include: (i) Expect Threshold set to 10; (ii) Word Size set to 28; (iii) Max matches in a query range set to 0; (iv) Match / Mismatch Scores set to 1, -2; (v) Gap Costs set to Linear; and (vi) the filter for low complexity regions being used. In some embodiments, the algorithm parameters used for BLASTP algorithm on the NCBI website include: (i) Expect Threshold set to 10; (ii) Word Size set to 3; (iii) Max matches in a query range set to 0; (iv) Matrix set to BLOSUM62; (v) Gap Costs set to Existence: 11 Extension: 1; and (vi) conditional compositional score matrix adjustment.

[0720] Percentage identity is obtained by determining the number of identical positions at which the sequences to be compared correspond, dividing this number by the number of positions compared (e.g., the number of positions in the reference sequence) and multiplying this result by 100.

[0721] In some embodiments, the degree of similarity or identity is given for a region which is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% of the entire length of the reference sequence. For example, if the reference amino acid sequenceconsists of 200 amino acid residues, the degree of identity is given for at least about 100, at least about 120, at least about 140, at least about 160, at least about 180, or about 200 amino acid residues, in some embodiments continuous amino acid residues. In some embodiments, the degree of similarity or identity is given for the entire length of the reference sequence.

[0722] Nucleic acid sequences or amino acid sequences having a particular degree of similarity or identity to a given nucleic acid sequence or amino acid sequence, respectively, may have at least one functional property of said given sequence, e.g., and in some instances, are functionally equivalent to said given sequence. One important property includes an immunogenic property, in particular when administered to a subject. In some embodiments, a nucleic acid sequence or amino acid sequence having a particular degree of similarity or identity to a given nucleic acid sequence or amino acid sequence is functionally equivalent to the given sequence.

[0723] Homologous amino acid sequences exhibit according to the present disclosure at least 40%, in particular at least 50%, at least 60%, at least 70%, at least 80%, at least 90% and preferably at least 95%, at least 98 or at least 99% identity of the amino acid residues.

[0724] The amino acid sequence variants described herein may readily be prepared by the skilled person, for example, by recombinant DNA manipulation. The manipulation of DNA sequences for preparing peptides or proteins having substitutions, additions, insertions or deletions, is described in detail in Sambrook et al. (1989), for example. Furthermore, the peptides and amino acid variants described herein may be readily prepared with the aid of known peptide synthesis techniques such as, for example, by solid phase synthesis and similar methods.

[0725] In one embodiment, a fragment or variant of an amino acid sequence (peptide or protein) is preferably a "functional fragment" or "functional variant". The term "functional fragment" or "functional variant" of an amino acid sequence relates to any fragment or variant exhibiting one or more functional properties identical or similar to those of the amino acid sequence from which it is derived, i.e., it is functionally equivalent. With respect to antigens or antigenic sequences, one particular function is one or more immunogenic activities displayed by the amino acid sequence from which the fragment or variant is derived. The term "functional fragment" or "functional variant", as used herein, in particular refers to a variant molecule or sequence that comprises an amino acid sequence that is altered by one or more amino acids compared to the amino acid sequence of the parent molecule or sequence and that is still capable of fulfilling one or more of the functions of the parent molecule or sequence, e.g., inducing 4-1BB activity. In one embodiment, the modifications in the amino acid sequence of the parent molecule or sequence do not significantly affect or alter the characteristics of the molecule or sequence. In different embodiments, the function of the functional fragment or functional variant may be reduced but still significantly present, e.g., immunogenicity of the functional variant may be at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the parent molecule or sequence. However, in other embodiments, immunogenicity of the functional fragment or functional variant may be enhanced compared to the parent molecule or sequence.An amino acid sequence (peptide, protein or polypeptide) "derived from" a designated amino acid sequence (peptide, protein or polypeptide) refers to the origin of the first amino acid sequence. Preferably, the amino acid sequence which is derived from a particular amino acid sequence has an amino acid sequence that is identical, essentially identical or homologous to that particular sequence or a fragment thereof. Amino acid sequences derived from a particular amino acid sequence may be variants of that particular sequence or a fragment thereof. For example, it will be understood by one of ordinary skill in the art that the antigens suitable for use herein may be altered such that they vary in sequence from the naturally occurring or native sequences from which they were derived, while retaining the desirable activity of the native sequences.

[0726] " Isolated" means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not "isolated", but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is "isolated". An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell. In a preferred embodiment, one or both of the multi-specific binding agents disclosed herein is in substantially purified form.

[0727] According to the present disclosure, an analog of a peptide or protein is a modified form of said peptide or protein from which it has been derived and has at least one functional property of said peptide or protein. E.g., a pharmacological active analog of a peptide or protein has at least one of the pharmacological activities of the peptide or protein from which the analog has been derived. Such modifications include any chemical modification and comprise single or multiple substitutions, deletions and / or additions of any molecules associated with the protein or peptide, such as carbohydrates, lipids and / or proteins or peptides. In one embodiment, "analogs" of proteins or peptides include those modified forms resulting from glycosylation, acetylation, phosphorylation, amidation, palmitoylation, myristoylation, isoprenylation, lipidation, alkylation, derivatization, introduction of protective / blocking groups, proteolytic cleavage or binding to an antibody or to another cellular ligand. The term "analog" also extends to all functional chemical equivalents of said proteins and peptides.

[0728] " Activation" or "stimulation", as used herein, refers to the state of an immune effector cell such as a T cell that has been sufficiently stimulated to induce detectable cellular proliferation. Activation can also be associated with initiation of signaling pathways, induced cytokine production, and detectable effector functions. The term "activated immune effector cells" (such as "activated T cells") refers to, among other things, immune effector cells (such as T cells) that are undergoing cell division.

[0729] The term "priming" refers to a process wherein an immune effector cell such as a T cell has its first contact with its specific antigen and causes differentiation into effector cells such as effector T cells. The term "clonal expansion" or "expansion" refers to a process wherein a specific entity is multiplied. In the context of the present disclosure, the term is preferably used in the context of an immunological response in which immune effector cells (such as lymphocytes) are stimulated, proliferate, and the specific immune effector cell (such as the specific lymphocyte) recognizing a target antigen is amplified.An "antigen" according to the present disclosure covers any substance that will elicit an immune response and / or any substance against which an immune response or an immune mechanism such as a cellular response is directed. This also includes situations wherein the antigen is processed into antigen peptides and an immune response or an immune mechanism is directed against one or more antigen peptides, in particular if presented in the context of MHC molecules. In one embodiment, an antigen is a disease-associated antigen, such as a tumor antigen, or an epitope derived from such antigen. The term "epitope" refers to an antigenic determinant in a molecule such as an antigen, i.e., to a part in or fragment of the molecule that is recognized by the immune system, for example, that is recognized by antibodies, T cells or B cells, in particular when presented in the context of MHC molecules. In one embodiment, "epitope" means a protein determinant capable of specific binding to an antibody. Epitopes usually consist of surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. The epitope may comprise amino acid residues directly involved in the binding and other amino acid residues, which are not directly involved in the binding, such as amino acid residues which are effectively blocked or covered by the specifically antigen-binding peptide (in other words, the amino acid residue is within the footprint of the specifically antigen-binding peptide).

[0730] An epitope of a protein preferably comprises a continuous or discontinuous portion of said protein and is preferably between about 5 and about 100, preferably between about 5 and about 50, more preferably between about 8 and about 0, most preferably between about 10 and about 25 amino acids in length, for example, the epitope may be preferably 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acids in length. It is particularly preferred that the epitope in the context of the present disclosure is a T cell epitope.

[0731] Terms such as "epitope", "fragment of an antigen", "immunogenic peptide" and "antigen peptide" are used interchangeably herein and preferably relate to an incomplete representation of an antigen which is preferably capable of eliciting an immune response against the antigen or a cell expressing or comprising and preferably presenting the antigen. Preferably, the terms relate to an immunogenic portion of an antigen. Preferably, it is a portion of an antigen that is recognized i.e., specifically bound) by a T cell receptor, in particular if presented in the context of MHC molecules. Certain preferred immunogenic portions bind to an MHC class I or class II molecule. The term "epitope" refers to a part or fragment of a molecule such as an antigen that is recognized by the immune system. For example, the epitope may be recognized by T cells, B cells or antibodies. An epitope of an antigen may include a continuous or discontinuous portion of the antigen and may be between about 5 and about 100, such as between about 5 and about 50, more preferably between about 8 and about 30, most preferably between about 8 and about 25 amino acids in length, for example, the epitope may be preferably 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acids in length. In oneembodiment, an epitope is between about 10 and about 25 amino acids in length. The term "epitope" includes T cell epitopes.

[0732] The term "optional" or "optionally" as used herein means that the subsequently described event, circumstance or condition may or may not occur, and that the description includes instances where said event, circumstance, or condition occurs and instances in which it does not occur.

[0733] As used herein "endogenous" refers to any material from or produced inside an organism, cell, tissue or system.

[0734] As used herein, the terms "linked", "fused", or "fusion" are used interchangeably. These terms refer to the joining together of two or more elements or components or domains.

[0735] The term "disease" (also referred to as "disorder" herein) refers to an abnormal condition that affects the body of an individual. A disease is often construed as a medical condition associated with specific symptoms and signs. A disease may be caused by factors originally from an external source, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune diseases. In humans, "disease" is often used more broadly to refer to any condition that causes pain, dysfunction, distress, social problems, or death to the individual afflicted, or similar problems for those in contact with the individual. In this broader sense, it sometimes includes injuries, disabilities, disorders, syndromes, infections, isolated symptoms, deviant behaviors, and atypical variations of structure and function, while in other contexts and for other purposes these may be considered distinguishable categories. Diseases usually affect individuals not only physically, but also emotionally, as contracting and living with many diseases can alter one's perspective on life, and one's personality.

[0736] The term "therapeutic treatment" relates to any treatment which improves the health status and / or prolongs (increases) the lifespan of an individual. Said treatment may eliminate the disease in an individual, arrest or slow the development of a disease in an individual, inhibit or slow the development of a disease in an individual, decrease the frequency or severity of symptoms in an individual, and / or decrease the recurrence in an individual who currently has or who previously has had a disease.

[0737] The terms "prophylactic treatment" or "preventive treatment" relate to any treatment that is intended to prevent a disease from occurring in an individual. The terms "prophylactic treatment" or "preventive treatment" are used herein interchangeably. Similarly, the term "method for preventing" in the context of progression of a disease, such as progression of a tumor or cancer, relates to any method that is intended to prevent the disease from progressing in an individual.

[0738] The terms "individual" and "subject" are used herein interchangeably. They refer to a human or another mammal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate), or any other nonmammal-animal, including birds (chicken), fish or any other animal species that can be afflicted with or is susceptible to a disease or disorder (e.g., cancer) but may or may not have the disease or disorder, or may have a need for prophylactic intervention such as vaccination, or may have a need for interventions such as by protein replacement. In many embodiments, the individual is a human being.Unless otherwise stated, the terms "individual" and "subject" do not denote a particular age, and thus encompass adults, elderlies, children, and newborns. In embodiments of the present disclosure, the "individual" or "subject" is a "patient".

[0739] The term "patient" means an individual or subject for treatment, in particular a diseased individual or subject.

[0740] The term "polynucleotide" or "nucleic acid", as used herein, is intended to include DNA and RNA such as genomic DNA, cDNA, mRNA, recombinantly produced and chemically synthesized molecules. A nucleic acid may be single-stranded or double-stranded. RNA includes in vitro transcribed RNA (IVT RNA) or synthetic RNA.

[0741] Nucleic acids may be comprised in a vector. The term "vector" as used herein includes any vectors known to the skilled person including plasmid vectors, cosmid vectors, phage vectors such as lambda phage, viral vectors such as retroviral, adenoviral or baculoviral vectors, or artificial chromosome vectors such as bacterial artificial chromosomes (BAC), yeast artificial chromosomes (YAC), or Pl artificial chromosomes (PAC). Said vectors include expression as well as cloning vectors. Expression vectors comprise plasmids as well as viral vectors and generally contain a desired coding sequence and appropriate DNA sequences necessary for the expression of the operably linked coding sequence in a particular host organism (e.g., bacteria, yeast, plant, insect, or mammal) or in in vitro expression systems. Cloning vectors are generally used to engineer and amplify a certain desired DNA fragment and may lack functional sequences needed for expression of the desired DNA fragments.

[0742] In one embodiment of the disclosure, a nucleic acid is expressed in cells of a subject treated to provide the encoded peptide or protein. In one embodiment, the nucleic acid is transiently expressed in cells of the subject. Thus, in one embodiment, the nucleic acid is not integrated into the genome of the cells. In one embodiment, the nucleic acid is RNA, preferably in vitro transcribed RNA.

[0743] The nucleic acids described herein may be recombinant and / or isolated molecules.

[0744] The term " RNA" relates to a nucleic acid molecule which includes ribonucleotide residues. The RNA can contain all or a majority of ribonucleotide residues. As used herein, "ribonucleotide" refers to a nucleotide with a hydroxyl group at the 2'-position of a p-D-ribofuranosyl group. RNA encompasses without limitation, double stranded RNA, single stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as modified RNA that differs from naturally occurring RNA by the addition, deletion, substitution and / or alteration of one or more nucleotides. Such alterations may refer to addition of non-nucleotide material to internal RNA nucleotides or to the end(s) of RNA. It is also contemplated that nucleotides in RNA may be nonstandard nucleotides, such as chemically synthesized nucleotides or deoxynucleotides. For the present disclosure, these altered RNAs are considered analogs of naturally-occurring RNA.

[0745] The RNA can be messenger RNA (mRNA) that relates to a RNA transcript which encodes a peptide or protein. As established in the art, mRNA generally contains a 5' untranslated region (5'-UTR), a peptidecoding region and a 3' untranslated region (3'-UTR). In some embodiments, the RNA is produced by in vitro transcription or chemical synthesis. In one embodiment, the mRNA is produced by in vitro transcription using a DNA template where DNA refers to a nucleic acid that contains deoxyribonucleotides.

[0746] The RNA can be in vitro transcribed RNA (IVT-RNA) and may be obtained by in vitro transcription of an appropriate DNA template. The promoter for controlling transcription can be any promoter for any RNA polymerase. A DNA template for in vitro transcription may be obtained by cloning of a nucleic acid, in particular cDNA, and introducing it into an appropriate vector for in vitro transcription. The cDNA may be obtained by reverse transcription of RNA.

[0747] The RNA can have modified nucleosides. In some embodiments, the RNA comprises a modified nucleoside in place of at least one (e.g., every) uridine. For example, the modified nucleoside is independently selected from pseudouridine (ψ), N1-methyl-pseudouridine (m1ψ), and 5-methyl-uridine (m5U). The modified nucleoside replacing one or more uridine in the RNA can be any one or more of 3-methyl-uridine (m3U), 5-methoxy-uridine (mo5U), 5-aza-uridine, 6-aza-uridine, 2-thio-5-aza-uridine, 2-thio-uridine (s2U), 4-thio-uridine (s4U), 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxy-uridine (ho5U), 5-aminoallyl-uridine, 5-halo-uridine (e.g., 5-iodo-uridine or 5-bromo-uridine), uridine 5-oxyacetic acid (cmo5U), uridine 5-oxyacetic acid methyl ester (mcmo5U), 5-carboxymethyl-uridine (cm5U), 1-carboxymethyl-pseudouridine, 5-carboxyhydroxymethyl-uridine (chm5U), 5-carboxyhydroxymethyl-uridine methyl ester (mchm5U), 5-methoxycarbonylmethyl-uridine (mcm5U), 5-methoxycarbonylmethyl-2-thio-uridine (mcm5s2U), 5-aminomethyl-2-thio-uridine (nm5s2U), 5-methylaminomethyl-uridine (mnm5U), 1-ethyl-pseudouridine, 5-methylaminomethyl-2-thio-uridine (mnm5s2U), 5-methylaminomethyl-2-seleno-uridine (mnm5se2U), 5-carbamoylmethyl-uridine (ncm5U), 5-carboxymethylaminomethyl-uridine (cmnm5U), 5-carboxymethylaminomethyl-2-thio-uridine (cmnm5s2U), 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyl-uridine (Tm5U), 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine(Tm5s2U), 1-taurinomethyl-4-thio-pseudouridine), 5-methyl-2-thio-uridine (m5s2U), 1-methyl-4-thio-pseudouridine (m1s4ψ), 4-thio-l-methyl-pseudouridine, 3-methyl-pseudouridine (m3ψ), 2-thio-l-methyl-pseudouridine, 1-methyl-l-deaza-pseudouridine, 2-thio-l-methyl-l-deaza-pseudouridine, dihydrouridine (D), dihydropseudouridine, 5,6-dihydrouridine, 5-methyl-dihydrouridine (m5D), 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxy-uridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, Nl-methyl-pseudouridine, 3-(3-amino-3-carboxypropyl)uridine (acp3U), l-methyl-3-(3-amino-3-carboxypropyl)pseudouridine (acp3ip), 5-(isopentenylaminomethyl)uridine (inm5U), 5-(isopentenylaminomethyl)-2-thio-uridine (inm5s2U), 1-thio-uridine, 2'-O-methyl-uridine (Um), 5,2'-O-dimethyl-uridine (m5Um), 2'-O-methyl-pseudouridine (ψm), 2-thio-2'-O-methyl-uridine (s2Um), 5-methoxycarbonylmethyl-2'-O-methyl-uridine (mcm5Um), 5-carbamoylmethyl-2'-O-methyl-uridine (ncm5Um), 5-carboxymethylaminomethyl-2'-O-methyl-uridine (cmnm5Um), 3,2'-O-dimethyl-uridine (m3Um), 5-(isopentenylaminomethyl)-2'-O-methyl-uridine (inm5Um), 1-thio-uridine,deoxythymidine, 2'-F-ara-uridine, 2'-F-uridine, 2'-OH-ara-uridine, 5-(2-carbomethoxyvinyl) uridine, 5-[3-(1-E-propenylamino)uridine, or any other modified uridine known in the art.

[0748] The RNA can comprise a 5'-cap. For example, the RNA does not have uncapped 5’-triphosphates. The RNA may be modified by a 5’- cap analog. The term "5’-cap" refers to a structure found on the 5’-end of an mRNA molecule and generally consists of a guanosine nucleotide connected to the mRNA via a 5’-to 5’-triphosphate linkage. In one possibility, this guanosine is methylated at the 7-position. Providing an RNA with a 5’-cap or 5’-cap analog may be achieved by in vitro transcription, in which the 5’-cap is co-transcriptionally expressed into the RNA strand, or may be attached to RNA post-transcriptionally using capping enzymes.

[0749] The RNA can comprise a capO, capl, or cap2. According to the present disclosure, the term "capO" means the structure "m7GpppN", wherein N is any nucleoside bearing an OH moiety at position 2’. The term "capl" means the structure "m7GpppNm", wherein Nm is any nucleoside bearing an OCH3 moiety at position 2’. The term "cap2" means the structure "m7GpppNmNm", wherein each Nm is independently any nucleoside bearing an OCH3 moiety at position 2’.

[0750] For example, the RNA can comprise a 5’-cap structure selected from the group consisting of m27'2'0G(5')ppSp(5’)G (in particular its DI diastereomer), m27'3'0G(5')ppp(5’)G, and m27'3' °Gppp(mi2'_°)ApG.

[0751] Also, the RNA can comprise a 5'-UTR and / or a 3'-UTR. The term "untranslated region" or " UTR" relates to a region in a DNA molecule which is transcribed but is not translated into an amino acid sequence, or to the corresponding region in an RNA molecule, such as an mRNA molecule. An untranslated region (UTR) can be present 5' (upstream) of an open reading frame (5'-UTR) and / or 3' (downstream) of an open reading frame (3'-UTR). A 5'-UTR, if present, is located at the 5' end, upstream of the start codon of a protein-encoding region. A 5'-UTR is downstream of the 5'-cap (if present), e.g. directly adjacent to the 5'-cap. A 3'-UTR, if present, is located at the 3' end, downstream of the termination codon of a protein-encoding region, but the term "3'-UTR" does preferably not include the poly(A) sequence. Thus, the 3'-UTR is upstream of the poly(A) sequence (if present), e.g. directly adjacent to the poly(A) sequence.

[0752] Also, the RNA can comprise a 3'-poly(A) sequence. As used herein, the term "poly(A) sequence" or "poly-A tail" refers to an uninterrupted or interrupted sequence of adenylate residues which is typically located at the 3' end of an RNA molecule. Poly(A) sequences are known to those of skill in the art and may follow the 3' UTR in the RNAs described herein. The poly(A) sequence may be of any length. In some embodiments, a poly(A) sequence comprises or consists of at least 20, at least 30, at least 40, at least 80, or at least 100 and up to 500, up to 400, up to 300, up to 200, or up to 150 nucleotides, and, in particular, about 110 nucleotides. In some embodiments, the poly(A) sequence only consists of A nucleotides. In some embodiments, the poly(A) sequence essentially consists of A nucleotides, but is interrupted by a random sequence of the four nucleotides (A, C, G, and U), as disclosed in WO 2016 / 005324 Al, hereby incorporated by reference. Such random sequence may be 5 to 50, 10 to 30,or 10 to 20 nucleotides in length. A poly(A) cassette present in the coding strand of DNA that essentially consists of dA nucleotides, but is interrupted by a random sequence having an equal distribution of the four nucleotides (dA, dC, dG, dT) and having a length of e.g. 5 to 50 nucleotides shows, on DNA level, constant propagation of plasmid DNA in E. coli and is still associated, on RNA level, with the beneficial properties with respect to supporting RNA stability and translational efficiency. In some embodiments, no nucleotides other than A nucleotides flank a poly(A) sequence at its 3' end, i.e., the poly(A) sequence is not masked or followed at its 3' end by a nucleotide other than A.

[0753] As used herein, the term "transcription" relates to a process, wherein the genetic code in a DNA sequence is transcribed into RNA. Subsequently, the RNA may be translated into peptide or protein. " Encoding" refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the noncoding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA. Similarly, RNA such as mRNA encodes a protein if translation of the RNA produces the protein in a cell or other biological system.

[0754] RNA may be naked or packaged, e.g., formulated in particles such as protein and / or lipid particles, e.g., lipid nanoparticles.

[0755] As used herein "endogenous" refers to any material from or produced inside an organism, cell, tissue or system.

[0756] As used herein, the term "exogenous" refers to any material introduced from or produced outside an organism, cell, tissue or system.

[0757] The term "expression" as used herein is defined as the transcription and / or translation of a particular nucleotide sequence.

[0758] Fc regions may have at their C-terminus a lysine. The origin of this lysine is a naturally occurring sequence found in humans from which these Fc regions are derived. During cell culture production of recombinant antibodies, this terminal lysine can be cleaved off by proteolysis by endogenous carboxypeptidase(s), resulting in a constant region having the same sequence but lacking the C-terminal lysine. For manufacturing purposes of antibodies, the DNA encoding this terminal lysine can be omitted from the sequence such that antibodies are produced without the lysine. Antibodies produced from nucleic acid sequences that either do, or do not encode a terminal lysine are substantially identical in sequence and in function since the degree of processing of the terminal lysine is typically high when e.g. using antibodies produced in CHO-based production systems (Dick, L. W. et al. Biotechnol. Bioeng.2008;100: 1132-1143). Hence, it is understood that proteins in accordance with the disclosure, such as antibodies, can be generated with or without encoding or having a terminal lysine.

[0759] Aspects and embodiments of the present disclosure

[0760] In a one aspect, the present disclosure provides a combination or a medical preparation, kit, or composition comprising: (a) a first binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and (b) a second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity. As demonstrated in the present disclosure, a combined treatment with the first binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction and with the second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity exhibited robust antitumor treatment activity that was superior to the treatment effect than either binding agent alone.

[0761] I. First binding agent of the combination or comprised with the medical preparation, kit, or composition

[0762] The binding region in the first binding agent which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction

[0763] One component of the anti-PD-1 / PD-LlxVEGF / VEGFR binding agent (first binding agent) is a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction. Thus, this first binding region comprises an antagonist of the PD-1 / PD-L1 interaction, such as an anti-PD-1 antibody, a PD-1 binding fragment thereof, an anti-PD-Ll antibody, or a PD-L1 binding fragment thereof.

[0764] Al. Anti-PD-1 antibodies or PD-1 binding fragments thereof

[0765] In some embodiments, the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises an anti-PD-1 antibody or a PD-1 binding fragment thereof.

[0766] In some embodiments, PD-1 is human PD-1, in particular human PD-1 comprising the sequence set forth in SEQ ID NO: 174, 175, or 176.

[0767] In some embodiments, the anti-PD-1 antibody or a PD-1 binding fragment thereof (anti-PD-1 antibody or fragment thereof) specifically binds to PD-1.In some embodiments, the anti-PD-1 antibody or fragment thereof is selected from the group consisting of Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Toripalimab, Retifanlimab, Jankistomig, and PD-1 binding fragments thereof.

[0768] In some embodiments, the anti-PD-1 antibody or fragment thereof is a monoclonal antibody or a fragment thereof.

[0769] In some embodiments, the anti-PD-1 antibody or fragment thereof is a humanized antibody. In some embodiments, the anti-PD-1 antibody or fragment thereof is a monoclonal humanized antibody. In some embodiments, the fragment of the anti-PD-1 antibody may be any antigen-binding fragment of the anti-PD-1 antibody, for example a Fab, a Fab', a F(ab')2, a Fv, a scFv, a Fab'-SH, an sdAb, or a VHH. In some embodiments, the anti-PD-1 antibody or fragment thereof is selected from a full-length anti-PD-1 antibody, an scFv of an anti-PD-1 antibody or a VHH of an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody or fragment thereof is an scFv of an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody or fragment thereof is a VHH of an anti-PD-1 antibody.

[0770] In some embodiments, the anti-PD-1 antibody or fragment thereof may comprise a variable region that specifically binds to PD-1. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a heavy chain variable region and / or a light chain variable domain. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a heavy chain variable region and a light chain variable domain. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a constant region, preferably derived from a human antibody, preferably the constant region is selected from the constant region of human IgGl, IgG2, IgG3 or IgG4. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a heavy chain and / or a light chain. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a heavy chain and a light chain. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of a heavy chain and a light chain as a single chain (scFv).

[0771] Exemplary anti-PD-1 antibody CDRs, variable region sequences, and heavy and light chain sequences are provided in Table 1, e.g., for anti-PD-1 antibodies Al, A2, A5, A6, A7, A8, and A10, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof is defined by one or more sequences of the anti-PD-1 antibody Al shown in Table 1.

[0772] In some embodiments, the CDRs are defined according to the IMGT numbering system. Thus, in some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 103, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 104, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 105, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of theamino acid sequence of SEQ ID NO: 106, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 107, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 108, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0773] In some embodiments, the CDRs are defined according to the Kabat numbering system. Thus, in some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 109, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 110, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 111, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 112, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 113, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 108, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0774] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the amino acid sequence comprises (i) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequencesset forth in: SEQ ID NO: 103, 104, 105, 106, 107, and 108, respectively, or (ii) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 109, 110, 111, 112, 113, and 108, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114, wherein the amino acid sequence comprises (i) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 103, 104, 105, 106, 107, and 108, respectively, or (ii) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 109, 110, 111, 112, 113, and 108, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 114. In some embodiments, the anti-PD-1 antibody or fragment thereof is an scFv comprising:

[0775] (i-la) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 103, 104, and 105, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 106, 107, and 108, respectively; (i-lb) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 109, 110, and 111, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 112, 113, and 108, respectively; (i-lc) the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 114;

[0776] (i-ld) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 114, and comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 103, 104, 105, 106, 107, and 108, respectively; or

[0777] (i-le) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 114, and comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 109, 110, 111, 112, 113, and 108, respectively.

[0778] In some alternative embodiments, the anti-PD-1 antibody or fragment thereof is defined by one or more sequences of the anti-PD-1 antibody A2 shown in Table 1.

[0779] In some embodiments, the CDRs are defined according to the Kabat numbering system. Thus, in some embodiments, a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 115, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 116, or a variant thereof having up to three amino acid substitutions, additionsor deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 117 or 118, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0780] In some embodiments, the CDRs are defined according to the IMGT numbering system. Thus, in some embodiments, a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 119, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 120, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 121 or 122, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0781] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 123, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 123, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the amino acid sequence comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 123, wherein the amino acid sequence comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively. Insome embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 123.

[0782] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 124, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 124, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the amino acid sequence comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 118, respectively, or (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 122, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 124, wherein the amino acid sequence comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 118, respectively, or (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 122, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 124.

[0783] Thus, in some embodiments, the anti-PD-1 antibody or fragment thereof is a VHH comprising:

[0784] (i-2a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 118, respectively;

[0785] (i-2b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively, or a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 122, respectively;

[0786] (i-2c) the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 123, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 123 preferably comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively; or(i-2d) the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 124, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 124 preferably comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 118, respectively, or comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 122, respectively.

[0787] In some embodiments, the anti-PD-1 antibody or fragment thereof is defined by one or more sequences of the anti-PD-1 antibody A5, A6, A7 or A8 shown in Table 1.

[0788] In some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 185, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 186, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 187, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 188, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 190, or a variant thereof having up to three amino acid substitutions, additions or deletions, (ii') a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 197, or a variant thereof having up to three amino acid substitutions, additions or deletions, (ii") a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 205, or a variant thereof having up to three amino acid substitutions, additions or deletions, or (ii'") a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 213, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 198, or a variant thereof having up to three amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0789] In some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 185, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 186, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 187, or a variant thereof having up to three amino acid substitutions, additionsor deletions, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 188, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 189, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 190, or a variant thereof having up to three amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0790] In some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 185, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 186, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 187, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 188, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 197, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 198, or a variant thereof having up to three amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0791] In some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 185, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 186, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 187, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 188, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 205, or a variant thereof having up to three amino acidsubstitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 206, or a variant thereof having up to three amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0792] In some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 185, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 186, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 187, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 188, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 213, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 214, or a variant thereof having up to three amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0793] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191. In some embodiments, theanti-PD-1 antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 191.

[0794] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 188, 189, and 190, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192, wherein the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 188, 189, and 190, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 192.

[0795] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 200 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 200 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 196, 197, and 198, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 200. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 196, 197, and 198, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 200.

[0796] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 208 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 208 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 204, 205, and 206, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 208. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 208, wherein the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 204, 205, and 206, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 208.

[0797] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VL comprises the CDR1, CDR2, and CDR3 sequences set forthin: SEQ ID NO: 212, 213, and 214, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216, wherein the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 212, 213, and 214, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 216.

[0798] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 215, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 188, 189, and 190, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191,and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 188, 189, and 190, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 191, and (II) comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 192.

[0799] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 200 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 200 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 193, 194, and 195, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 196, 197, and 198, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 200. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequenceidentity to the amino acid sequence of SEQ ID NO: 200, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 188, 197, and 198, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 191, and (II) comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 200.

[0800] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 208 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 208 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 188, 205, and 190, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 208. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 208, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and the VL comprisesthe CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 188, 205, and 190, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 191, and (II) comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 208.

[0801] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 188, 213, and 214, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 188, 213, and 214, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising orconsisting of the amino acid sequence of SEQ ID NO: 191, and (II) comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 216.

[0802] Thus, in some embodiments, the anti-PD-1 antibody or fragment thereof is a fragment of a humanized anti-PD-1 antibody comprising:

[0803] (i-5a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 191, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 192;

[0804] (i-5b) a heavy chain variable region (VH) comprising the HCDR.1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 188, 189, and 190, respectively; (i-5c) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192;

[0805] (i-5d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 188, 189, and 190, respectively; or

[0806] (i-5e) a heavy chain variable region (VH) comprising or consisting of the amino acid sequence of SEQ ID NO: 191, and a light chain variable region (VL) comprising or consisting of the amino acid sequence of SEQ ID NO: 192.

[0807] Thus, in some embodiments, the anti-PD-1 antibody or fragment thereof is a fragment of a humanized anti-PD-1 antibody comprising:

[0808] (i-6a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 199, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 200;

[0809] (i-6b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 193, 194, and 195, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 196, 197, and 198, respectively;(i-6c) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 199, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 200;

[0810] (i-6d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 199, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ of ID NO: 200, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 193, 194, and 195, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 196, 197, and 198, respectively; or

[0811] (i-6e) a heavy chain variable region (VH) comprising or consisting of the amino acid sequence of SEQ ID NO: 199, and a light chain variable region (VL) comprising or consisting of the amino acid sequence of SEQ ID NO: 200.

[0812] Thus, in some embodiments, the anti-PD-1 antibody or fragment thereof is a fragment of a humanized anti-PD-1 antibody comprising:

[0813] (i-7a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 207, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 208;

[0814] (i-7b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 201, 202, and 203, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 204, 205, and 206, respectively; (i-7c) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 190, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 195;

[0815] (i-7d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 207, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acidsequence of SEQ ID NO: 208, wherein the VH comprises the HCDR.1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 201, 202, and 203, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 204, 205, and 206, respectively; or

[0816] (i-7e) a heavy chain variable region (VH) comprising or consisting of the amino acid sequence of SEQ ID NO: 207, and a light chain variable region (VL) comprising or consisting of the amino acid sequence of SEQ ID NO: 208.

[0817] Thus, in some embodiments, the anti-PD-1 antibody or fragment thereof is a fragment of a humanized anti-PD-1 antibody comprising:

[0818] (i-8a) a heavy chain variable region (VH) comprising the HCDR.1, HCDR2, and HCDR3 sequences of SEQ ID NO: 215, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 216;

[0819] (i-8b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 209, 210, and 211, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 212, 213, and 214, respectively; (i-8c) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 215, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216;

[0820] (i-8d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 215, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 209, 210, and 211, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 212, 213, and 214, respectively; or

[0821] (i-8e) a heavy chain variable region (VH) comprising or consisting of the amino acid sequence of SEQ ID NO: 215, and a light chain variable region (VL) comprising or consisting of the amino acid sequence of SEQ ID NO: 216.

[0822] In some alternative embodiments, the anti-PD-1 antibody or fragment thereof is defined by one or more sequences of the anti-PD-1 antibody A10 shown in Table 1.In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (a) a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 237, and / or a light chain variable region (VL) comprising the CDR.1, CDR2, and CDR3 sequences of SEQ ID NO: 238.

[0823] In some embodiments, the CDRs are defined according to the Kabat numbering system. Thus, in some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 230, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 232, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 234, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 143, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 144, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 236, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0824] In some embodiments, the CDRs are defined according to the IMGT numbering system. Thus, in some embodiments, (I) a VH of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 231, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 233, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 235, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 149, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 150, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 236, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up tothree amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0825] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VH comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, or (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 231,233, and 235, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, wherein the VH comprises (i) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, or (ii) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 231, 233, and 235, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 237. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VL comprises (i) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively, or (ii) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%,or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238, wherein the VL comprises (i) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively, or (ii) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 238.

[0826] In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-1 antibody or fragment thereof comprisesa (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein (i) the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively, or (ii) the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 231, 233, and 235, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to theamino acid sequence of SEQ ID NO: 237, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238, wherein (i) the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively, or (ii) the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 231, 233, and 235, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively. In some embodiments, the anti-PD-1 antibody or fragment thereof comprises (I) a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 237, and (II) comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 238.

[0827] Thus, in some embodiments, the anti-PD-1 antibody or fragment thereof is a fragment (preferably, a Fab fragment) of an anti-PD-1 antibody comprising:

[0828] (i-10a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 237, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 238;

[0829] (i-10b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively; (i-10c) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 231, 233, and 235, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively; (i-10d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238;

[0830] (i-10e) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively; or(i-10f) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238, wherein the VH comprises the HCDR.1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 231, 233, and 235, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively.

[0831] In some embodiments, the anti-PD-1 antibody or fragment thereof (e.g., a Fab fragment thereof) comprises a CHI domain, preferably comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 249.

[0832] In some embodiments, the anti-PD-1 antibody or fragment thereof (e.g., a Fab fragment thereof) comprises a CL domain, preferably comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 155.

[0833] In some embodiments, the anti-PD-1 antibody or fragment thereof (e.g., a Fab fragment thereof) comprises an IgG4 Fc region comprising a S228P mutation. Amino acids are numbered according to the EU numbering (EU-index) as set forth in Kabat (Kabat, E. A.; National Institutes of Health (U. S.) Office of the Director. Sequences of Proteins of Immunological Interest, 5th ed.; DIANE Publishing: Collingdale, PA, USA, 1991). For example, these may correspond to S228P in SEQ ID NO: 250. In some embodiments, the anti-PD-1 antibody or fragment thereof (e.g., a Fab fragment thereof) comprises a Fc domain comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 250.

[0834] A2. Anti-PD-Ll antibodies or PD-L1 binding fragments thereof

[0835] In some embodiments, the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises an anti-PD-Ll antibody or a PD-L1 binding fragment thereof.

[0836] In some embodiments, PD-L1 is human PD-L1, in particular human PD-L1 comprising the sequence set forth in SEQ ID NO: 177, 178, 179, or 180.

[0837] In some embodiments, the anti-PD-Ll antibody or a PD-L1 binding fragment thereof (anti-PD-Ll antibody or fragment thereof) specifically binds to PD-L1.In some embodiments, the anti-PD-Ll antibody or fragment thereof is selected from the group consisting of Atezolizumab, Durvalumab, Avelumab, Sotiburafusp alpha, Palverafusp, and PD-L1 binding fragments thereof.

[0838] In some embodiments, the anti-PD-Ll antibody or fragment thereof is a monoclonal antibody or a fragment thereof.

[0839] In some embodiments, the anti-PD-Ll antibody or fragment thereof is a humanized antibody. In some embodiments, the anti-PD-Ll antibody or fragment thereof is a monoclonal humanized antibody. In some embodiments, the fragment of the anti-PD-Ll antibody may be any antigen-binding fragment of the anti-PD-Ll antibody, for example a Fab, a Fab', a F(ab')2, a Fv, a scFv, a Fab'-SH, an sdAb, or a VHH. In some embodiments, the anti-PD-Ll antibody or fragment thereof is selected from a full-length anti-PD-Ll antibody, an scFv of an anti-PD-Ll antibody or a VHH of an anti-PD-Ll antibody. In some embodiments, the anti-PD-Ll antibody or fragment thereof is a VHH of an anti-PD-Ll antibody.

[0840] In some embodiments, the anti-PD-Ll antibody or fragment thereof may comprise a variable region that specifically binds to PD-L1. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a heavy chain variable region and / or a light chain variable domain. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a heavy chain variable region and a light chain variable domain. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a constant region, preferably derived from a human antibody, preferably the constant region is selected from the constant region of human IgGl, IgG2, IgG3 or IgG4. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a heavy chain and / or a light chain. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a heavy chain and a light chain. In some embodiments, the anti-PD-Ll antibodyorfragment thereof comprises of a heavy chain and a light chain as a single chain (scFv). In some embodiments, the anti-PD-Ll antibody or fragment thereof is a VHH of an anti-PD-Ll antibody.

[0841] Exemplary anti-PD-Ll antibody CDRs, variable region sequences, and heavy and light chain sequences are provided in Table 1, e.g., for anti-PD-Ll antibodies A3 and A4, respectively.

[0842] In some embodiments, the anti-PD-Ll antibody or fragment thereof is defined by one or more sequences of the anti-PD-Ll antibody A3 shown in Table 1.

[0843] In some embodiments, the CDRs are defined according to the Kabat numbering system. Thus, in some embodiments, a VH of the anti-PD-Ll antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 125, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 126, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 127, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system. In some embodiments, the CDR variantshave up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0844] In some embodiments, the CDRs are defined according to the IMGT numbering system. Thus, in some embodiments, a VH of the anti-PD-Ll antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 128, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 129, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 130, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0845] In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 131, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 131, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the amino acid sequence comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 125, 126, and 127, respectively, or (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 128, 129, and 130, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises or consists of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 131, wherein the amino acid sequence comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 125, 126, and 127, respectively, or (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 128, 129, and 130, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 131.

[0846] Thus, in some embodiments, the anti-PD-Ll antibody or fragment thereof is a VHH comprising:(i-3a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 125, 126, and 127, respectively;

[0847] (i-3b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 128, 129, and 130, respectively; or

[0848] (i-3c) the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 131, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 131 preferably comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 125, 126, and 127, respectively, or comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 128, 129, and 130, respectively.

[0849] In some alternative embodiments, the anti-PD-Ll antibody or fragment thereof is defined by one or more sequences of the anti-PD-Ll antibody A4 shown in Table 1.

[0850] In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises (a) a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 138, and / or a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 139. In some embodiments, (I) a VH of the anti-PD-Ll antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 132, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 133, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 134, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-1 antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 135, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 136, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 137, or a variant thereof having up to three amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0851] In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%,at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and / or one or more {e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and / or one or more e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VH comprises the CDR.1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, wherein the VH comprises the CDR.1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 138.

[0852] In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 139 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 139 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 139. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 139, wherein the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 139.In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 139 and / or one or more (e.g., 1, 2, 3,, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 139 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 139. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 139, wherein the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises (I) a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 138, and (II) comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 139.

[0853] Thus, in some embodiments, the anti-PD-Ll antibody or fragment thereof is a fragment of a humanized anti-PD-Ll antibody comprising:(i-4a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 138, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 139;

[0854] (i-4b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively; (i-4c) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 139; or

[0855] (i-4d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 139, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively.

[0856] In some alternative embodiments, the anti-PD-Ll antibody or fragment thereof is defined by one or more sequences of the anti-PD-Ll antibody A9 shown in Table 1.

[0857] In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises (a) a heavy chain variable region (VH) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 273, and / or a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 274. In some embodiments, the CDRs are defined according to the IMGT numbering system. Thus, in some embodiments, (I) a VH of the anti-PD-Ll antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 262, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 263, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 264, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-Ll antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 265, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 266, or a variant thereof having up to three amino acid substitutions, additions or deletions;and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 267, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the IMGT numbering system. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0858] In some embodiments, the CDRs are defined according to the Kabat numbering system. Thus, in some embodiments, (I) a VH of the anti-PD-Ll antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 268, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 269, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 270, or a variant thereof having up to three amino acid substitutions, additions or deletions, and / or (II) a VL of the anti-PD-Ll antibody or fragment thereof comprises: (i) a CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 271, or a variant thereof having up to three amino acid substitutions, additions or deletions; (ii) a CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 272, or a variant thereof having up to three amino acid substitutions, additions or deletions; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 267, or a variant thereof having up to three amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system. In some embodiments, the CDR variants have up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variants have up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variants have up to three amino acid substitutions. In some embodiments, the CDR variants have up to two amino acid substitutions. In some embodiments, the CDR variants have up to one amino acid substitution.

[0859] In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 273, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 273, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VH comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 262, 263, and 264, respectively, or (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 268, 269, and 270, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequencehaving at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 273. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 273, wherein the VH comprises (i) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 262, 263, and 264, respectively, or (ii) the CDR.1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 268, 269, and 270, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 273. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 274 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 274 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein the VL comprises (i) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 265, 266, and 267, respectively, or (ii) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 271, 272, and 267, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 274. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 274, wherein the VL comprises (i) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 265, 266, and 267, respectively, or (ii) the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 271, 272, and 267, respectively. In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 274.

[0860] In some embodiments, the anti-PD-Ll antibody or fragment thereof comprises (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 273, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acidsequence of SEQ ID NO: 274 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof. In some embodiments, the anti-PD-L1 antibody or fragment thereof comprises a (I) a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 273, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, and (II) a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 274 and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof, wherein (i) the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 262, 263, and 264, respectively, and the VL comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 265, 266, and 267, respectively, or (ii) the VH comprises the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 268, 269, and 270, respectively, and the VL compris...

Claims

CLAIMS:

1. A combination of:(a) a first binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and(b) a second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

2. A combination for use as a medicament, wherein the combination comprises a first binding agent and a second binding agent, wherein:(a) the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and(b) the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

3. A method of treating cancer in a subject comprising administering to the subject a first binding agent and a second binding agent, wherein:(a) the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and(b) the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

4. A binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, for use in a method of treating cancer in a subject, the method comprising administering to the subject the binding agent and a further binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

5. A binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity, for use in a method of treating cancer in a subject, the method comprising administering to the subject the binding agent and a further binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction.

6. A first binding agent and a second binding agent for use in a method of treating cancer in a subject, wherein the method comprises administering to the subject the first binding agent and the second binding agent, wherein the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and wherein the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

7. A medical preparation, combination, kit, or composition comprising a first binding agent and a second binding agent, wherein:(a) the first binding agent comprises (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and(b) the second binding agent comprises (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity, or a kit comprising:(c) in one or more vials (a) a first binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and (b) a second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity; or d) a first binding agent and a second binding agent; or(i) a first binding agent and instructions for combining the first binding agent with the second binding agent for use in a treatment of cancer in a subject; or(ii) a second binding agent and instructions for combining the second binding agent with a first binding agent for use in a treatment of cancer in a subject;wherein the first binding agent comprises (i') a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii') a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction and / or wherein the second binding agent comprising (I") a third binding region which binds to EpCAM; and (ii") a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

8. The combination of claim 1, the combination for use of claim 2, the method of claim 3, the binding agent for use of claim 4 or 5, the first and second binding agents for use of claim 6, or the medical preparation, combination, kit, or composition of claim 7, wherein the first binding region whichbinds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises an anti-PD-L1 antibody or a PD-L1 binding fragment thereof.

9. The combination of claim 8, the combination for use of claim 8, the method of claim 8, the binding agent for use of claim 8, the first and second binding agents for use of claim 8, or the medical preparation, combination, kit, or composition of claim 8, wherein the anti-PD-1 antibody is selected from the group consisting of Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab, Toripalimab, Retifanlimab, Jankistomig, and PD-1 binding fragments thereof.

10. The combination of claim 1, 8 or 9, the combination for use of claim 2, 8 or 9, the method of claim 3, 8 or 9, the binding agent for use of claim 4, 5, 8 or 9, the first and second binding agents for use of claim 6, 8 or 9, or the medical preparation, combination, kit, or composition of claim 7 to 9, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises:(i-la) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 103, 104, and 105, respectively, and / or a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 106, 107, and 108, respectively; (i-lb) a heavy chain variable region (VH) comprising the HCDR.1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 109, 110, and 111, respectively, and / or a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 112, 113, and 108, respectively; (i-lc) the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114;(i-ld) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114, and comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 103, 104, 105, 106, 107 and 108, respectively; or(i-le) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114, and comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 109, 110, 111, 112, 113, and 108, respectively.

11. The combination of claim 1, 8 or 9, the combination for use of claim 2, 8 or 9, the method of claim 3, 8 or 9, the binding agent for use of claim 4, 5, 8 or 9, the first and second binding agents for use of claim 6, 8 or 9, or the medical preparation, combination, kit, or composition of claim 7 to 9, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises:(i-2a) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 118, respectively (e.g., the first binding region comprises a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 118, respectively);(i-2b) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively, or the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 122, respectively (e.g., the first binding region comprises a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively, or a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 122, respectively);(i-2c) the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 123, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 123 preferably comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively; or(i-2d) the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 124, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 124 preferably comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 118, respectively, or comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 122, respectively.

12. The combination of claim 1, 8 or 9, the combination for use of claim 2, 8 or 9, the method of claim 3, 8 or 9, the binding agent for use of any one of claims 4 to 5, 8 or 9, the first and second binding agents for use of claim 6, 8 or 9, or the medical preparation, combination, kit, or composition of claim 7 to 9, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises:(i-5a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 191, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 192;(i-5b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 188, 189, and 190, respectively; (i-5c) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192;(i-5d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 191, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 185, 186, and 187, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 188, 189, and 190, respectively; or(i-5e) a heavy chain variable region (VH) comprising or consisting of the amino acid sequence of SEQ ID NO: 191, and a light chain variable region (VL) comprising or consisting of the amino acid sequence of SEQ ID NO: 192.

13. The combination of claim 1, 8 or 9, the combination for use of claim 2, 8 or 9, the method of claim 3, 8 or 9, the binding agent for use of claim 4, 5, 8 or 9, the first and second binding agents for use of claim 6, 8 or 9, or the medical preparation, combination, kit, or composition of claim 7 to 9, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises:(i-6a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 199, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 200;(i-6b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 193, 194, and 195, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 196, 197, and 198, respectively; (i-6c) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 199, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, atleast 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 200;(i-6d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 199, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ of ID NO: 200, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 193, 194, and 195, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 196, 197, and 198, respectively; or(i-6e) a heavy chain variable region (VH) comprising or consisting of the amino acid sequence of SEQ ID NO: 199, and a light chain variable region (VL) comprising or consisting of the amino acid sequence of SEQ ID NO: 200.

14. The combination of claim 1, 8 or 9, the combination for use of claim 2, 8 or 9, the method of claim 3, 8 or 9, the binding agent for use of claim 4, 5, 8 or 9, the first and second binding agents for use of claim 6, 8 or 9, or the medical preparation, combination, kit, or composition of claim 7 to 9, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises:(i-7a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 207, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 208;(i-7b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 201, 202, and 203, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 204, 205, and 206, respectively; (i-7c) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 190, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 195;(i-7d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 207, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 208, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequencesset forth in: SEQ ID NO: 201, 202, and 203, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 204, 205, and 206, respectively; or(i-7e) a heavy chain variable region (VH) comprising or consisting of the amino acid sequence of SEQ ID NO: 207, and a light chain variable region (VL) comprising or consisting of the amino acid sequence of SEQ ID NO: 208.

15. The combination of claim 1, 8 or 9, the combination for use of claim 2, 8 or 9, the method of claim 3, 8 or 9, the binding agent for use of claim 4, 5, 8 or 9, the first and second binding agents for use of claim 6, 8 or 9, or the medical preparation, combination, kit, or composition of claim 7 to 9, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises:(i-8a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 215, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 216;(i-8b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 209, 210, and 211, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 212, 213, and 214, respectively; (i-8c) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 215, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216;(i-8d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 215, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 209, 210, and 211, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 212, 213, and 214, respectively; or(i-8e) a heavy chain variable region (VH) comprising or consisting of the amino acid sequence of SEQ ID NO: 215, and a light chain variable region (VL) comprising or consisting of the amino acid sequence of SEQ ID NO: 216.

16. The combination of claim 1, 8 or 9, the combination for use of claim 2, 8 or 9, the method of claim 3, 8 or 9, the binding agent for use of claim 4, 5, 8 or 9, the first and second binding agents foruse of claim 6, 8 or 9, or the medical preparation, combination, kit, or composition of claim 7 to 9, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises:(i-10a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 237, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 238;(i-10b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively; (i-10c) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 231, 233, and 235, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively; (i-10d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238;(i-10e) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively; or(i-10f) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 231, 233, and 235, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively.

17. The combination of claim 1, the combination for use of claim 2, the method of claim 3, the binding agent for use of claim 4 or 5, the first and second binding agents for use of claim 6, or themedical preparation, combination, kit, or composition of claim 7, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises an anti-PD-L1 antibody or a PD-L1 binding fragment thereof.

18. The combination of claim 17, the combination for use of claim 17, the method of claim 17, the binding agent for use of claim 17, the first and second binding agents for use of claim 17, or the medical preparation, combination, kit, or composition of claim 17, wherein the anti-PD-Ll antibody is selected from the group consisting of Atezolizumab, Durvalumab, Avelumab, Sotiburafusp alpha, Palverafusp, and PD-L1 binding fragments thereof.

19. The combination of claim 1, 17 or 18, the combination for use of claim 2, 17 or 18, the method of claim 3, 17 or 18, the binding agent for use of claim 4, 5, 17, or 18, the first and second binding agents for use of claim 6, 17 or 18, or the medical preparation, combination, kit, or composition of claim 7, 17, or 18, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises:(i-3a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 125, 126, and 127, respectively;(i-3b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 128, 129, and 130, respectively; or(i-3c) the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 131, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 131 preferably comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 125, 126, and 127, respectively, or comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 128, 129, and 130, respectively.

20. The combination of claim 8 to 19, the combination for use of claim 8 to 19, the method of claim 8 to 19, the binding agent for use of claim 8 to 19, the first and second binding agents for use of claim 8 to 19, or the medical preparation, combination, kit, or composition of claim 8 to 19, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises a single-chain fragment (e.g., scFv) or a VHH.

21. The combination of claim 1, 17, or 18, the combination for use of claim 2, 17 or 18, the method of claim 3, 17, or 18, the binding agent for use of claim 4, 5, 17, or 18, the first and second binding agents for use of claim 6, 17, or 18, or the medical preparation, combination, kit, or composition of claim 7, 17 or 18, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises:(i-4a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 138, and / or a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 139;(i-4b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively, and / or a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively; (i-4c) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 139; or(i-4d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 139, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively.

22. The combination of claim 1, 17, or 18, the combination for use of claim 2, 17 or 18, the method of claim 3, 17, or 18, the binding agent for use of claim 4, 5, 17, or 18, the first and second binding agents for use of claim 6, 17, or 18, or the medical preparation, combination, kit, or composition of claim 7, 17 or 18, wherein the first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction comprises:(i-9a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 273, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 274;(i-9b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 262, 263, and 264, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 265, 266, and 267, respectively; (i-9c) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 268, 269, and 270, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 271, 272, and 267, respectively;277(i-9d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 273, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 274;(i-9e) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 273, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 274, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 262, 263, and 264, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 265, 266, and 267, respectively; or(i-9f) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 273, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 274, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 268, 269, and 270, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 271, 272, and 267, respectively.

23. The combination of any one of claims 1 and 8 to 22, the combination for use of any one of claims 2 and 8 to 22, the method of any one of claims 3 and 8 to 22, the binding agent for use of any one of claims 4, 5 and 8 to 22, the first and second binding agents for use of any one of claims 6 and 8 to 22, or the medical preparation, combination, kit, or composition of any one of claims 7 to 22, wherein the second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction comprises an anti-VEGF antibody (preferably an anti-VEGF-A antibody) or a VEGF binding fragment thereof.

24. The combination of any one of claims 1 and 8 to 23, the combination for use of any one of claims 2 and 8 to 23, the method of any one of claims 3 and 8 to 23, the binding agent for use of any one of claims 4, 5 and 8 to 23, the first and second binding agents for use of any one of claims 6 and 8 to 23, or the medical preparation, combination, kit, or composition of any one of claims 7 to 23, wherein the anti-VEGF antibody is selected from Bevacizumab, Ramucirumab, Ranibizumab, and VEGF binding fragments thereof.

25. The combination of any one of claims 1 and 8 to 24, the combination for use of any one of claims 2 and 8 to 24, the method of any one of claims 3 and 8 to 24, the binding agent for use of anyone of claims 4, 5 and 8 to 24, the first and second binding agents for use of any one of claims 6 and 8 to 24, or the medical preparation, combination, kit, or composition of any one of claims 7 to 24, wherein the second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction comprises:(ii-la) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 151, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 152;(ii-lb) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively; (ii-lc) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively; (ii-1d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 152;(ii-1e) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 152, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively;(ii-1f) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 152, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively;(ii-1g) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156 and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157; (ii-1h) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156 and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively; or(ii-1i) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156 and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

26. The combination of any one of claims 1 and 8 to 24, the combination for use of any one of claims 2 and 8 to 24, the method of any one of claims 3 and 8 to 24, the binding agent for use of any one of claims 4, 5 and 8 to 24, the first and second binding agents for use of any one of claims 6 and 8 to 24, or the medical preparation, combination, kit, or composition of any one of claims 7 to 24, wherein the second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction comprises:(ii-2a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 247, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 248;(ii-2b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 243, 141, and 245, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively; (ii-2c) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 244, 147, and 246, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively;(ii-2d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 247, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 248;(ii-2e) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 247, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 248, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 243, 141, and 245, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively; or(ii-2f) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 247, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 248, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 244, 147, and 246, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively.

27. The combination of any one of claims 1 and 8 to 24, the combination for use of any one of claims 2 and 8 to 24, the method of any one of claims 3 and 8 to 24, the binding agent for use of any one of claims 4, 5 and 8 to 24, the first and second binding agents for use of any one of claims 6 and 8 to 24, or the medical preparation, combination, kit, or composition of any one of claims 7 to 24, wherein the second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction comprises:(ii-2'a) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 151, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 248;(ii-2'b) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively;(ii-2'c) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively; (ii-2'd) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 248;(ii-2'e) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 248, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively; or(ii-2'f) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 248, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively.

28. The combination of any one of claims 1 and 8 to 27, the combination for use of any one of claims 2 and 8 to 27, the method of any one of claims 3 and 8 to 27, the binding agent for use of any one of claims 4, 5 and 8 to 27, the first and second binding agents for use of any one of claims 6 and 8 to 27, or the medical preparation, combination, kit, or composition of any one of claims 7 to 27, wherein the second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction is in the format of a full-length antibody or a VEGF binding antibody fragment thereof.

29. The combination of any one of claims 1 and 8 to 22, the combination for use of any one of claims 2 and 8 to 22, the method of any one of claims 3 and 8 to 22, the binding agent for use of any one of claims 4, 5 and 8 to 22, the first and second binding agents for use of any one of claims 6 and 8 to 22, or the medical preparation, combination, kit, or composition of any one of claims 7 to 22, wherein the second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and whichantagonizes the VEGF / VEGFR interaction comprises a VEGFR domain, such as a VEGFR-1 domain comprising the amino acid sequence of SEQ ID NO: 158, a VEGFR-2 domain comprising the amino acid sequence of SEQ ID NO: 159, a VEGFR-3a domain comprising the amino acid sequence of SEQ ID NO: 160, a VEGFR-3b domain comprising the amino acid sequence of SEQ ID NO: 251, or a combination thereof.

30. The combination of any one of claims 1, 8 to 22 and 29, the combination for use of any one of claims 2, 8 to 22 and 29, the method of any one of claims 3, 8 to 22 and 29, the binding agent for use of any one of claims 4, 5, 8 to 22 and 29, the first and second binding agents for use of any one of claims 6, 8 to 22 and 29, or the medical preparation, combination, kit, or composition of any one of claims 7 to 22 and 29, wherein the second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction comprises at least one VEGFR-1 domain, or at least one VEGFR-2 domain, or at least one VEGFR-3a domain, or at least one VEGFR-1 domain and at least one VEGFR-2 domain, such as two VEGFR-1 domains, or two VEGFR-2 domains, or two VEGFR-1 domains and two VEGFR-2 domains, or two VEGFR-3a domains.

31. The combination of any one of claims 1, 8 to 22, 29 and 30, the combination for use of any one of claims 2, 8 to 22, 29 and 30, the method of any one of claims 3, 8 to 22, 29 and 30, the binding agent for use of any one of claims 4, 5, 8 to 22, 29 and 30, the first and second binding agents for use of any one of claims 6, 8 to 22, 29 and 30, or the medical preparation, combination, kit, or composition of any one of claims 7 to 22, 29 and 30, wherein the second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction comprises:(ii-3a) the amino acid sequence of SEQ ID NO: 158 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 158;(ii-3b) the amino acid sequence of SEQ ID NO: 159 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 159;(ii-3c) the amino acid sequence of SEQ ID NO: 160 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 160 (such as the amino acid sequence of SEQ ID NO: 251);(ii-3d) the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 161;(ii-3e) the amino acid sequence of SEQ ID NO: 251 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 251; or(ii-3f) the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 162.

32. The combination of any one of claims 1 and 8 to 31, the combination for use of any one of claims 2 and 8 to 31, the method of any one of claims 3 and 8 to 31, the binding agent for use of any one of claims 4, 5 and 8 to 31, the first and second binding agents for use of any one of claims 6 and 8 to 31, or the medical preparation, combination, kit, or composition of any one of claims 7 to 31, wherein the first binding agent is a multispecific antibody, such as a bispecific antibody.

33. The combination of claim 32, the combination for use of claim 32, the method of claim 32, the binding agent for use of claim 32, the first and second binding agents for use of claim 32, or the medical preparation, combination, kit, or composition of claim 32, wherein the first binding region of the multispecific antibody binds to PD-L1 and the second binding region binds to VEGF, preferably to VEGF-A.

34. The combination of claim 32 or 33, the combination for use of claim 32 or 33, the method of claim 32 or 33, the binding agent for use of claim 32 or 33, the first and second binding agents for use of claim 32 or 33, or the medical preparation, combination, kit, or composition of claim 32 or 33, wherein the multispecific antibody comprises an anti-VEGF antibody and at least one anti-PD-Ll single domain antibody, preferably an anti-VEGF antibody and two anti-PD-Ll single domain antibodies, more preferably an anti-VEGF antibody and two anti-PD-Ll VHHs.

35. The combination of claim 34, the combination for use of claim 34, the method of claim 34, the binding agent for use of claim 34, the first and second binding agents for use of claim 34, or the medical preparation, combination, kit, or composition of claim 34, wherein each heavy chain of the anti-VEGF antibody is terminally fused to an anti-PD-Ll single domain antibody, preferably via a linker.

36. The combination of any one of claims 1 and 8 to 35, the combination for use of any one of claims 2 and 8 to 35, the method of any one of claims 3 and 8 to 35, the binding agent for use of any one of claims 4, 5 and 8 to 35, the first and second binding agents for use of claim 6 and 8 to 35, or the medical preparation, combination, kit, or composition of any one of claims 7 to 35, wherein the first binding agent comprises:(A) (1) at least one anti-PD-Ll single domain antibody comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 125, 126, and 127, respectively, or comprising the HCDR.1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 128, 129, and 130, respectively; and / or (2) an anti-VEGF antibody comprising (i) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively; or (ii) a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQID NO: 146, 147, and 148, respectively, and a VL comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively; or(B) (1) at least one anti-PD-Ll single domain antibody comprising the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 131, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 131 preferably comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 125, 126, and 127, respectively, or the HCDR.1, HCDR2, and HCDR3 sequences set forth in: 128, 129, and 130, respectively; and / or (2) an anti-VEGF antibody comprising (i) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively; or (ii) a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and a VL comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

37. The combination of claim 36, the combination for use of claim 36, the method of claim 36, the binding agent for use of claim 36, the first and second binding agents for use of claim 36, or the medical preparation, combination, kit, or composition of claim 36, wherein the anti-VEGF antibody comprises: (ii-1d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 152;(ii-1e) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 152, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively;(ii-1f) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, atleast 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence SEQ ID NO: 152, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and the VL comprises the LCDR.1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively;(ii-1g) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156, and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157;(ii-1h) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156, and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively; or(ii-1i) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156, and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

38. The combination of any one of claims 1 and 8 to 37, the combination for use of any one of claims 2 and 8 to 37, the method of any one of claims 3 and 8 to 37, the binding agent for use of any one of claims 4, 5 and 8 to 37, the first and second binding agents for use of any one of claims 6 and 8 to 37, or the medical preparation, combination, kit, or composition of any one of claims 7 to 37, wherein the first binding agent comprises (A) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 163, and (B) a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein (I) the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and (ii) the HCDR1, HCDR2,and HCDR3 sequences set forth in: SEQ ID NO: 125, 126, and 127, respectively, or the HC comprises (i') the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and (ii') the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 128, 129, and 130, respectively, and (II) the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively, or the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

39. The combination of any one of claims 1 and 8 to 38, the combination for use of any one of claims 2 and 8 to 38, the method of any one of claims 3 and 8 to 38, the binding agent for use of any one of claims 4, 5 and 8 to 38, the first and second binding agents for use of any one of claims 6 and 8 to 38, or the medical preparation, combination, kit, or composition of any one of claims 7 to 38, wherein the first binding agent comprises (A) two heavy chains (HCs) each comprising the amino acid sequence of SEQ ID NO: 163, and (B) two light chains (LCs) each comprising the amino acid sequence of SEQ ID NO: 157.

40. The combination of claim 32, the combination for use of claim 32, the method of claim 32, the binding agent for use of claim 32, the first and second binding agents for use of claim 32, or the medical preparation, combination, kit, or composition of claim 32, wherein the first binding region of the multispecific antibody binds to PD-1 and the second binding region binds to VEGF, preferably to VEGF-A.

41. The combination of claim 40, the combination for use of claim 40, the method of claim 40, the binding agent for use of claim 40, the first and second binding agents for use of claim 40, or the medical preparation, combination, kit, or composition of claim 40, wherein the multispecific antibody comprises an anti-VEGF antibody and at least one anti-PD-1 scFv antibody, preferably an anti-VEGF antibody and two anti-PD-1 scFv antibodies.

42. The combination of claim 41, the combination for use of claim 41, the method of claim 41, the binding agent for use of claim 41, the first and second binding agents for use of claim 41, or the medical preparation, combination, kit, or composition of claim 41, wherein each heavy chain of the anti-VEGF antibody is terminally fused to an anti-PD-1 scFv antibody, preferably via a linker.

43. The combination of any one of claims 40 to 42, the combination for use of any one of claims 40 to 42, the method of any one of claims 40 to 42, the binding agent for use of any one of claims 40 to 42, the first and second binding agents for use of any one of claims 40 to 42, or the medical preparation, combination, kit, or composition of any one of claims 40 to 42, wherein the binding agent comprises:(A) (1) at least one anti-PD-1 scFv antibody comprising a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 103, 104, and 105, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 106, 107, and 108, respectively, and (2) an anti-VEGF antibody comprising a heavychain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively;(B) (1) at least one anti-PD-1 scFv antibody comprising a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 109, 110, and 111, respectively, and a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 112, 113, and 108, respectively, and (2) an anti-VEGF antibody comprising a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively;(C) (1) at least one anti-PD-1 scFv antibody comprising the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114 preferably comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 103, 104, 105, 106, 107, and 108, respectively, and (2) an anti-VEGF antibody comprising a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively; or(D) (1) at least one anti-PD-1 scFv antibody comprising the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114 preferably comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 109, 110, 111, 112, 113, and 108, respectively, and (2) an anti-VEGF antibody comprising a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively.

44. The combination of any one of claims 40 to 43, the combination for use of any one of claims 40 to 43, the method of any one of claims 40 to 43, the binding agent for use of any one of claims 40 to 43, the first and second binding agents for use of any one of claims 40 to 43, or the medical preparation, combination, kit, or composition of any one of claims 40 to 43, wherein the anti-VEGF antibody comprises:(ii-1d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 152;(ii-1e) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 152, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively;(ii-1f) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 152, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively;(ii-1g) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156, and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157;(ii-1h) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156, and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively; or(ii-1i) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156, and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

45. The combination of any one of claims 40 to 44, the combination for use of any one of claims 40 to 44, the method of any one of claims 40 to 44, the binding agent for use of any one of claims 40 to 44, the first and second binding agents for use of any one of claims 40 to 44, or the medical preparation, combination, kit, or composition of any one of claims 40 to 44, wherein the binding agent comprises (A) at least one heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 164, and (B) at least one light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein (I) the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and (ii) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 109, 110, 111, 112, 113, and 108, respectively, or the HC comprises (i') the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and (ii') the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 103, 104, 105, 106, 107, and 108, respectively, and (II) the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively, or the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

46. The combination of any one of claims 40 to 45, the combination for use of any one of claims 40 to 45, the method of any one of claims 40 to 45, the binding agent for use of any one of claims 40 to 45, the first and second binding agents for use of any one of claims 40 to 45, or the medical preparation, combination, kit, or composition of any one of claims 40 to 45, wherein the binding agent comprises (A) two heavy chains (HCs) each comprising the amino acid sequence of SEQ ID NO: 164, and (B) two light chains (LCs) each comprising the amino acid sequence of SEQ ID NO: 157.

47. The combination of claim 40, the combination for use of claim 40, the method of claim 40, the binding agent for use of claim 40, the first and second binding agents for use of claim 40, or the medical preparation, combination, kit, or composition of claim 40, wherein the multispecific antibody comprises an anti-VEGF antibody and at least one anti-PD-1 single domain antibody, preferably an anti-VEGF antibody and at least two anti-PD-1 single domain antibodies, more preferably an anti-VEGF antibody and at least two anti-PD-1 VHHs.

48. The combination of claim 47, the combination for use of claim 47, the method of claim 47, the binding agent for use of claim 47, the first and second binding agents for use of claim 47, or the medical preparation, combination, kit, or composition of claim 47, wherein each heavy chain of the anti-VEGF antibody is terminally fused to an anti-PD-1 single domain antibody, preferably via a linker.

49. The combination of any one of claims 40, 47, and 48, the combination for use of any one of claims 40, 47, and 48, the method of any one of claims 40, 47, and 48, the binding agent for use of any one of claims 40, 47, and 48, the first and second binding agents for use of any one of claims 40, 47, and 48, or the medical preparation, combination, kit, or composition of any one of claims 40, 47, and 48, wherein the binding agent comprises:(A) (1) at least one anti-PD-1 single domain antibody comprising a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 118, respectively; and (2) an anti-VEGF antibody comprising a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively;(B) (1) at least one anti-PD-1 single domain antibody comprising a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively, or VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 122, respectively; and (2) an anti-VEGF antibody comprising a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively;(C) (1) at least one anti-PD-1 single domain antibody comprising the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 123, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 123 preferably comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively, and (2) an anti-VEGF antibody comprising (i) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively, or (ii) a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and a VL comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively; or(D) (1) at least one anti-PD-1 single domain antibody comprising the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 124, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 124 preferably comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 118, respectively, or the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 119, 120, and 122, respectively, and (2) an anti-VEGF antibody comprising (i) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and a light chain variable region (VL) comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively, or (ii) a VH comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and a VL comprising the CDR1, CDR2, and CDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

50. The combination of any one of claims 40 and 47 to 49, the combination for use of any one of claims 40 and 47 to 49, the method of any one of claims 40 and 47 to 49, the binding agent for use of any one of claims 40 and 47 to 49, the first and second binding agents for use of any one of claims 40 and 47 to 49, or the medical preparation, combination, kit, or composition of any one of claims 40 and 47 to 49, wherein the anti-VEGF antibody comprises:(ii-1d) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 152;(ii-1e) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 152, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 143, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively;(ii-1f) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, atleast 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 152, wherein the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively;(ii-1g) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156, and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157;(ii-1h) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156, and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively; or(ii-1i) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 156, and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

51. The combination of any one of claims 40 and 47 to 50, the combination for use of any one of claims 40 and 47 to 50, the method of any one of claims 40 and 47 to 50, the binding agent for use of any one of claims 40 and 47 to 50, the first and second binding agents for use of any one of claims 40 and 47 to 50, or the medical preparation, combination, kit, or composition of any one of claims 40 and 47 to 50, wherein the binding agent comprises (A) at least one heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 165, and (B) at least one light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein (I) the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively,and (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or the HC comprises (i') the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and (ii') the HCDR1, HCDR2, and HCDR3, sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively, and (II) the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively, or the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

52. The combination of any one of claims 40 and 47 to 50, the combination for use of any one of claims 40 and 47 to 50, the method of any one of claims 40 and 47 to 50, the binding agent for use of any one of claims 40 and 47 to 50, the first and second binding agents for use of any one of claims 40 and 47 to 50, or the medical preparation, combination, kit, or composition of any one of claims 40 and 47 to 50, wherein the binding agent comprises (A) at least one heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 166, and (B) at least one light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein (I) the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 117, respectively, or the HC comprises (i') the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and (ii') the HCDR1, HCDR2, and HCDR3, sequences set forth in: SEQ ID NO: 119, 120, and 121, respectively, and (II) the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively, or the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

53. The combination of any one of claims 40 and 47 to 50, the combination for use of any one of claims 40 and 47 to 50, the method of any one of claims 40 and 47 to 50, the binding agent for use of any one of claims 40 and 47 to 50, the first and second binding agents for use of any one of claims 40 and 47 to 50, or the medical preparation, combination, kit, or composition of any one of claims 40 and 47 to 50, wherein the binding agent comprises (A) at least one heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 167, and (B) at least one light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 157, wherein (I) the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and (ii) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 115, 116, and 118, respectively, or the HC comprises (i') the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and (ii') the HCDR1, HCDR2, and HCDR3, sequences set forth in: SEQ ID NO: 119, 120, and 122, respectively, and (II) the LC comprises the LCDR1, LCDR2, and LCDR3sequences set forth in: SEQ ID NO: 143, 144, and 145, respectively, or the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 145, respectively.

54. The combination of any one of claims 40 and 47 to 53, the combination for use of any one of claims 40 and 47 to 53, the method of any one of claims 40 and 47 to 53, the binding agent for use of any one of claims 40 and 47 to 53, the first and second binding agents for use of any one of claims 40 and 47 to 53, or the medical preparation, combination, kit, or composition of any one of claims 40 and 47 to 53, wherein the binding agent comprises (A) two heavy chains (HCs) each comprising the amino acid sequence of SEQ ID NO: 165, the amino acid sequence of SEQ ID NO: 166, or the amino acid sequence of SEQ ID NO: 167, and (B) two light chains (LCs) each comprising the amino acid sequence of SEQ ID NO: 157.

55. The combination of claim 40, the combination for use of claim 40, the method of claim 40, the binding agent for use of claim 40, the first and second binding agents for use of claim 40, or the medical preparation, combination, kit, or composition of claim 40, wherein the multispecific antibody comprises at least one Fab fragment of an anti-VEGF antibody and at least one Fab fragment of an anti-PD-1 antibody, preferably at least two Fab fragments of an anti-VEGF antibody and at least two Fab fragments of an anti-PD-1 antibody, more preferably two Fab fragments of an anti-VEGF antibody and two Fab fragments of an anti-PD-1 antibody.

56. The combination of claim 55, the combination for use of claim 55, the method of claim 55, the binding agent for use of claim 55, the first and second binding agents for use of claim 55, or the medical preparation, combination, kit, or composition of claim 55, wherein the two Fab fragments of the anti-VEGF antibody are the same; and / or the two Fab fragments of the anti-PD-1 antibody are the same.

57. The combination of claim 55 or 56, the combination for use of claim 55 or 56, the method of claim 55 or 56, the binding agent for use of claim 55 or 56, the first and second binding agents for use of claim 55 or 56, or the medical preparation, combination, kit, or composition of claim 55 or 56, wherein the at least one Fab fragment of the anti-PD-1 antibody is terminally fused to the at least one Fab fragment of the anti-VEGF antibody, preferably via a linker.

58. The combination of any one of claims 55 to 57, the combination for use of any one of claims 55 to 57, the method of any one of claims 55 to 57, the binding agent for use of any one of claims 55 to 57, the first and second binding agents for use of any one of claims 55 to 57, or the medical preparation, combination, kit, or composition of any one of claims 55 to 57, wherein the multispecific antibody comprises a heavy chain comprising at least one heavy chain Fd fragment of the anti-PD-1 antibody and at least one heavy chain Fd fragment of the anti-VEGF antibody, preferably of the anti-VEGF antibody 2.

59. The combination of claim 58, the combination for use of claim 58, the method of claim 58, the binding agent for use of claim 58, the first and second binding agents for use of claim 58, or the medical preparation, combination, kit, or composition of claim 58, wherein the heavy chain comprises from N toC terminal direction (i) a heavy chain Fd fragment of an anti-PD-1 antibody followed by a heavy chain Fd fragment of the anti-VEGF antibody, preferably of the anti-VEGF antibody 2; or (ii) a heavy chain Fd fragment of an anti-VEGF antibody, preferably of the anti-VEGF antibody 2, followed by a heavy chain Fd fragment of the anti-PD-1 antibody.

60. The combination of claim 58 or 59, the combination for use of claim 58 or 59, the method of claim 58 or 59, the binding agent for use of claim 58 or 59, the first and second binding agents for use of claim 58 or 59, or the medical preparation, combination, kit, or composition of claim 58 or 59, wherein the anti-PD-lxVEGF antibody comprises (i) two heavy chains (HCs) each comprising (a) a Fab fragment of the anti-PD-1 antibody, preferably the Fab fragment of the anti-PD-1 antibody A10, and (b) a Fab fragment of the anti-VEGF antibody, preferably of the anti-VEGF antibody 2; and (ii) four light chains (LCs), wherein each Fab fragment of the anti-VEGF antibody is fused to the Fab fragment of the anti-PD-1 antibody through a linker comprising the amino acid sequence of SEQ ID NO: 259 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 259.

61. The combination of any one of claims 55 to 60, the combination for use of any one of claims 55 to 60, the method of any one of claims 55 to 60, the binding agent for use of any one of claims 55 to 60, the first and second binding agents for use of any one of claims 55 to 60, or the medical preparation, combination, kit, or composition of any one of claims 55 to 60, wherein the the multispecific antibody comprises two Fab fragments of the anti-PD-1 antibody and two Fab fragments of the anti-VEGF antibody, preferably wherein (i) the two Fab fragments of the anti-PD-1 antibody are the same; (ii) the two Fab fragments of the anti-VEGF antibody are the same; and / or (iii) the two Fab fragments of the anti-PD-1 antibody are each fused to an Fc region, preferably to an Fc region of IgG4 or an Fc region derived from IgG4.

62. The combination of any one of claims 55 to 61, the combination for use of any one of claims 55 to 61, the method of any one of claims 55 to 61, the binding agent for use of any one of claims 55 to 61, the first and second binding agents for use of any one of claims 55 to 61, or the medical preparation, combination, kit, or composition of any one of claims 55 to 61, wherein the multispecific antibody comprises (i) a CHI domain, preferably comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 249; (ii) a CL domain, preferably comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 155; and / or (iii) an IgG4 Fc region comprising a S228P mutation, preferably an IgG4 Fc region comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 250.

63. The combination of any one of claims 55 to 62, the combination for use of any one of claims 55 to 62, the method of any one of claims 55 to 62, the binding agent for use of any one of claims 55 to 62, the first and second binding agents for use of any one of claims 55 to 62, or the medical preparation, combination, kit, or composition of any one of claims 55 to 62, wherein the multispecific antibody comprises:(A) (1) at least one anti-PD-1 VH comprising the amino acid sequence of SEQ ID NO: 237 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, preferably comprises the HCDR.1, HCDR2, HCDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, or the HCDR1, HCDR2, HCDR3 sequences set forth in SEQ ID NO: 231, 233, and 235, respectively; and / or (2) at least one anti-VEGF VH comprising the amino acid sequence of SEQ ID NO: 151 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 151, preferably comprising (i) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, or the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and / or a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively; or (ii) a VL comprising the comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively;(B) (1) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 253 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 253, and / or one or more amino acid additions, deletions and / or substitutions in a framework region thereof; and (2) a light chain sequence comprising the amino acid sequence of SEQ ID NO: 252 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 252, and / or one or more amino acid additions, deletions and / or substitutions in a framework region thereof;(C) (1) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 253, and (2) a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 252, wherein the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and (ii) the HCDR1, HCDR2, HCDR3 sequences set forth in: SEQID NO: 230, 232, and 234, respectively, and the LC comprises the LCDR.1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively;(C') (1)a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 253, and (2) a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 252, wherein the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and (ii) the HCDR1, HCDR2, HCDR3 sequences set forth in: SEQ ID NO: 231, 233, and 235, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively;(D) (1) an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 253 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 253; and (2) an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 252 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 252;(E) (1) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 253; and (2) a light chain sequence comprising the amino acid sequence of SEQ ID NO: 252; or(F) (1) two heavy chains each comprising the amino acid sequence of SEQ ID NO: 253; and (2) four light chains each comprising the amino acid sequence of SEQ ID NO: 252.

64. The combination of any one of claims 55 to 63, the combination for use of any one of claims 55 to 63, the method of any one of claims 55 to 63, the binding agent for use of any one of claims 55 to 63, the first and second binding agents for use of any one of claims 55 to 63, or the medical preparation, combination, kit, or composition of any one of claims 55 to 63, wherein the multispecific antibody comprises:(A) (1) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 254 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 254, and / or one or more amino acid additions, deletions and / or substitutions in a framework region thereof; and (2) a light chain sequence comprising the amino acid sequence of SEQ ID NO: 252 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 252, and / or one or more amino acid additions, deletions and / or substitutions in a framework region thereof;(B) (1) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 254, and (2) a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 252, wherein the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 140, 141, and 142, respectively, and (ii) the HCDR1, HCDR2, HCDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively;(B') (1) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 254, and (B') a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 252, wherein the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 146, 147, and 148, respectively, and (ii) the HCDR1, HCDR2, HCDR3 sequences set forth in: SEQ ID NO: 231, 233, and 235, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively;(C) (1) an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 254 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 254; and (2) an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 252 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 252;(D) (1) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 254; and (2) a light chain sequence comprising the amino acid sequence of SEQ ID NO: 252; or(E) (1) two heavy chains each comprising the amino acid sequence of SEQ ID NO: 254; and (2) four light chains each comprising the amino acid sequence of SEQ ID NO: 252.

65. The combination of any one of claim 55 to 63, the combination for use of any one of claim 55 to 63, the method of any one of claim 55 to 63, the binding agent for use of any one of claim 55 to 63, the first and second binding agents for use of any one of claim 55 to 63, or the medical preparation, combination, kit, or composition of any one of claim 55 to 63, wherein the multispecific antibody comprises:(A) (1) at least one anti-PD-1 VH comprising the amino acid sequence of SEQ ID NO: 237 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237 preferably comprises the HCDR1, HCDR2, HCDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, or the HCDR1, HCDR2, HCDR3 sequences set forth in SEQ ID NO: 231, 233, and 235, respectively; and / or (2) an anti-VEGF VH comprising the amino acidsequence of SEQ ID NO: 247 or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 247, wherein the amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 247 preferably comprises (i) a heavy chain variable region (VH) comprising the HCDR.1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 243, 141, and 245, respectively, or the HCDR.1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 244, 147, and 246; and / or a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively; or (ii) a VL comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively; (B) (1) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 255 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 255, and / or one or more amino acid additions, deletions and / or substitutions in a framework region thereof; and (2) a light chain sequence comprising the amino acid sequence of SEQ ID NO: 252 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 252, and / or one or more amino acid additions, deletions and / or substitutions in a framework region thereof;(C) (1) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 255, and (2) a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 252, wherein the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 243, 141, and 245, respectively, and (ii) the HCDR1, HCDR2, HCDR3 sequences set forth in: SEQ ID NO: 230, 232, and 234, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 143, 144, and 236, respectively;(C') (1) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 255, and (2) a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 252, wherein the HC comprises (i) the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 244, 147, and 246, respectively, and (ii) the HCDR1, HCDR2, HCDR3 sequences set forth in: SEQ ID NO: 231, 233, and 235, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 149, 150, and 236, respectively;(D) (1) an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 255 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to theamino acid sequence of SEQ ID NO: 255; and (2) an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 252 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 252;(E) (1) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 255; and (2) a light chain sequence comprising the amino acid sequence of SEQ ID NO: 252; or(F) (1) two heavy chains each comprising the amino acid sequence of SEQ ID NO: 255; and (ii) four light chains each comprising the amino acid sequence of SEQ ID NO: 252.

66. The combination of claim 32, the combination for use of claim 32, the method of claim 32, the binding agent for use of claim 32, the first and second binding agents for use of claim 32, or the medical preparation, combination, kit, or composition of claim 32, wherein the first binding region of the multispecific antibody binds to PD-L1 and the second binding region comprises at least one VEGFR domain.

67. The combination of claim 66, the combination for use of claim 66, the method of claim 66, the binding agent for use of claim 66, the first and second binding agents for use of claim 66, or the medical preparation, combination, kit, or composition of claim 66, wherein the multispecific antibody comprises a fusion protein comprising an anti-PD-Ll antibody and the at least one VEGFR domain.

68. The combination of claim 67, the combination for use of claim 67, the method of claim 67, the binding agent for use of claim 67, the first and second binding agents for use of claim 67, or the medical preparation, combination, kit, or composition of claim 67, wherein:(i) the at least one VEGR domain is terminally fused to the heavy chain of the anti-PD-Ll antibody, preferably via a linker;(ii) the anti-PD-Ll antibody comprises a full-length anti-PD-Ll antibody; and / or(iii) the anti-PD-Ll antibody is a humanized antibody.

69. The combination of any one of claims 66 to 68, the combination for use of any one of claims 66 to 68, the method of any one of claims 66 to 68, the binding agent for use of any one of claims 66 to 68, the first and second binding agents for use of any one of claims 66 to 68, or the medical preparation, combination, kit, or composition of any one of claims 66 to 68, wherein the binding agent comprises:(A) (1) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 138, and / or a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 139; and (2) at least one VEGFR domain comprising the amino acid sequence of SEQ ID NO: 159;(B) (1) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively, and / or a light chain variable region (VL) comprisingthe LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively; and (2) at least one VEGFR domain comprising the amino acid sequence of SEQ ID NO: 160; or (C) (1) a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 138, and a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 139, wherein preferably the VH comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively, and the VL comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively; and (2) at least one VEGFR domain comprising the amino acid sequence of SEQ ID NO: 160.

70. The combination of any one of claims 66 to 69, the combination for use of any one of claims 66 to 69, the method of any one of claims 66 to 69, the binding agent for use of any one of claims 66 to 69, the first and second binding agents for use of any one of claims 66 to 69, or the medical preparation, combination, kit, or composition of any one of claims 66 to 69, wherein the binding agent comprises (A) at least one heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 168, and (B) at least one light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 169, wherein the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively.

71. The combination of any one of claims 66 to 70, the combination for use of any one of claims 66 to 70, the method of any one of claims 66 to 70, the binding agent for use of any one of claims 66 to 70, the first and second binding agents for use of any one of claims 66 to 70, or the medical preparation, combination, kit, or composition of any one of claims 66 to 70, wherein the binding agent comprises (A) at least one heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 170, and (B) at least one light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 169, wherein the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 132, 133, and 134, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 135, 136, and 137, respectively.

72. The combination of any one of claims 66 to 71, the combination for use of any one of claims 66 to 71, the method of any one of claims 66 to 71, the binding agent for use of any one of claims 66to 71, the first and second binding agents for use of any one of claims 66 to 71, or the medical preparation, combination, kit, or composition of any one of claims 66 to 71, wherein the binding agent comprises (A) two heavy chains (HCs) each comprising the amino acid sequence of SEQ ID NO: 168 or the amino acid sequence of SEQ ID NO: 170, and (B) two light chains (LCs) each comprising the amino acid sequence of SEQ ID NO: 169.

73. The combination of any one of claims 66 to 68, the combination for use of any one of claims 66 to 68, the method of any one of claims 66 to 68, the binding agent for use of any one of claims 66 to 68, the first and second binding agents for use of any one of claims 66 to 68, or the medical preparation, combination, kit, or composition of any one of claims 66 to 68, wherein the binding agent comprises:(A) (1) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences of SEQ ID NO: 273, and / or a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID NO: 274 and (2) at least one VEGFR domain comprising or consisting of the amino acid sequence shown in SEQ ID NO: 251, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 251;(B) (1) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 262, 263, and 264, respectively, and / or a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 265, 266, and 267, respectively; and (2) at least one VEGFR domain comprising or consisting of the amino acid sequence shown in SEQ ID NO: 251, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 251; or(C) (1) a heavy chain variable region (VH) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 268, 269, and 270, respectively, and / or a light chain variable region (VL) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 271, 272, and 267, respectively; and (2) at least one VEGFR domain comprising or consisting of the amino acid sequence shown in SEQ ID NO: 251, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 251.

74. The combination of any one of claims 66 to 68 and 73, the combination for use of any one of claims 66 to 68 and 73, the method of any one of claims 66 to 68 and 73, the binding agent for use of any one of claims 66 to 68 and 73, the first and second binding agents for use of any one of claims 66 to 68 and 73, or the medical preparation, combination, kit, or composition of any one of claims 66 to 68 and 73, wherein the binding agent comprises:(A) (1) a heavy chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 256 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 256, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and (2) alight chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 257 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 257, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof;(B) (1) a heavy chain (HC) comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 256, and (2) a light chain (LC) comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 257, wherein (i) the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 262, 263, and 264, respectively, and the LC comprises the LCDR.1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 265, 266, and 267, respectively, or (ii) the HC comprises the HCDR.1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 268, 269, and 270, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 271, 272, and 267, respectively; or(C) (1) a heavy chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 256 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 256; and (2) a light chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 257 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 257.

75. The combination of any one of claims 66 to 68 and 73, the combination for use of any one of claims 66 to 68 and 73, the method of any one of claims 66 to 68 and 73, the binding agent for use of any one of claims 66 to 68 and 73, the first and second binding agents for use of any one of claims 66 to 68 and 73, or the medical preparation, combination, kit, or composition of any one of claims 66 to 68 and 73, wherein the binding agent comprises:(A) (1) a heavy chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 258 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 258, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof; and (2) a light chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 257 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 257, and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and / or substitutions in a framework region thereof;(B) (1) a heavy chain (HC) comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 258, and (2) a light chain (LC) comprisingor consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 257, wherein (i) the HC comprises the HCDR1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 262, 263, and 264, respectively, and the LC comprises the LCDR.1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 265, 266, and 267, respectively, or (ii) the HC comprises the HCDR.1, HCDR2, and HCDR3 sequences set forth in: SEQ ID NO: 268, 269, and 270, respectively, and the LC comprises the LCDR1, LCDR2, and LCDR3 sequences set forth in: SEQ ID NO: 271, 272, and 267, respectively; or(C) (1) a heavy chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 258 or an amino acid sequence comprising or consisting of at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 258; and (2) a light chain sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 257 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 257.

76. The combination of any one of claims 66 to 68 and 73 to 75, the combination for use of any one of claims 66 to 68 and 73 to 75, the method of any one of claims 66 to 68 and 73 to 75, the binding agent for use of any one of claims 66 to 68 and 73 to 75, the first and second binding agents for use of any one of claims 66 to 68 and 73 to 75, or the medical preparation, combination, kit, or composition of any one of claims 66 to 68 and 73 to 75, wherein the binding agent comprises (1) two heavy chains each comprising or consisting of the amino acid sequence of SEQ ID NO: 256 or the amino acid sequence of SEQ ID NO: 258; and (2) two light chains each comprising or consisting of the amino acid sequence of SEQ ID NO: 257.

77. The combination of claim 32, the combination for use of claim 32, the method of claim 32, the binding agent for use of claim 32, the first and second binding agents for use of claim 32, or the medical preparation, combination, kit, or composition of claim 32, wherein the first binding region of the multispecific antibody binds to PD-1 and the second binding region binds to VEGFR, preferably VEGFR2, preferably wherein the first binding region and the second binding region are separate, or overlap, partially or completely.

78. The combination of claim 77, the combination for use of claim 77, the method of claim 77, the binding agent for use of claim 77, the first and second binding agents for use of claim 77, or the medical preparation, combination, kit, or composition of claim 77, wherein the multispecific antibody comprises an IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2 immunoglobulin constant region, preferably wherein the multispecific antibody comprises an immunologically inert immunoglobulin constant region.

79. The combination of claim 77 or 78, the combination for use of claim 77 or 78, the method of claim 77 or 78, the binding agent for use of claim 77 or 78, the first and second binding agents for use of claim 77 or 78, or the medical preparation, combination, kit, or composition of claim 77 or 78, wherein the multispecific antibody comprises (I) a VH comprising: (i) a HCDR1 comprising or consisting of theamino acid sequence of SEQ ID NO: 185; (ii) a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 186; and (iii) a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 187, and / or (II) a VL comprising: (i) a LCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 188; (ii) a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 189, (ii') a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 197, (ii") a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 205, or (ii'") a LCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 213; and (iii) a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 214.

80. The combination of any one of claims 77 to 79, the combination for use of any one of claims 77 to 79, the method of any one of claims 77 to 79, the binding agent for use of any one of claims 77 to 79, the first and second binding agents for use of any one of claims 77 to 79, or the medical preparation, combination, kit, or composition of any one of claims 77 to 79, wherein the multispecific antibody comprises a VH comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 215; and / or a VL comprising or consisting of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 192, 200, 208, or 216.

81. The combination of any one of claims 77 to 80, the combination for use of any one of claims 77 to 80, the method of any one of claims 77 to 80, the binding agent for use of any one of claims 77 to 80, the first and second binding agents for use of any one of claims 77 to 80, or the medical preparation, combination, kit, or composition of any one of claims 77 to 80, wherein the multispecific antibody comprises a VH comprising or consisting of the amino acid sequence of SEQ ID NO: 215; and / or a VL comprising or consisting of the amino acid sequence of SEQ ID NO: 192, 200, 208, or 216.

82. The combination of any one of claims 1 and 8 to 81, the combination for use of any one of claims 2 and 8 to 81, the method of any one of claims 3 and 8 to 81, the binding agent for use of any one of claims 4, 5 and 8 to 81, the first and second binding agents for use of any one of claims 6 and 8 to 81, or the medical preparation, combination, kit, or composition of any one of claims 7 to 81, wherein the third binding region which binds to EpCAM comprises an anti-EpCAM antibody or an EpCAM binding fragment thereof.

83. The combination of any one of claims 1 and 8 to 82, the combination for use of any one of claims 2 and 8 to 82, the method of any one of claims 3 and 8 to 82 the binding agent for use of any one of claims 4, 5 and 8 to 82, the first and second binding agents for use of any one of claims 6 and 8 to 82, or the medical preparation, combination, kit, or composition of any one of claims 7 to 82, wherein the third binding region binding to EpCAM comprises a heavy chain variable region (VH) comprising a HCDR3 sequence comprising the sequence as set forth in SEQ ID NO: 4.

84. The combination of any one of claims 1 and 8 to 83, the combination for use of any one of claims 2 and 8 to 83, the method of any one of claims 3 and 8 to 83, the binding agent for use of any one of claims 4, 5 and 8 to 83, the first and second binding agents for use of any one of claims 6 and 8 to 83, or the medical preparation, combination, kit, or composition of any one of claims 7 to 83, wherein the third binding region binding to EpCAM comprises a heavy chain variable region (VH) comprising a HCDR2 sequence comprising the sequence as set forth in SEQ ID NO: 3.

85. The combination of any one of claims 1 and 8 to 84, the combination for use of any one of claims 2 and 8 to 84, the method of any one of claims 3 and 8 to 84, the binding agent for use of any one of claims 4, 5 and 8 to 84, the first and second binding agents for use of any one of claims 6 and 8 to 84, or the medical preparation, combination, kit, or composition of any one of claims 7 to 84, wherein the third binding region binding to EpCAM comprises a heavy chain variable region (VH) comprising a HCDR1 sequence comprising the sequence as set forth in SEQ ID NO: 2.

86. The combination of any one of claims 1 and 8 to 85, the combination for use of any one of claims 2 and 8 to 85, the method of any one of claims 3 and 8 to 85, the binding agent for use of any one of claims 4, 5 and 8 to 85, the first and second binding agents for use of any one of claims 6 and 8 to 85, or the medical preparation, combination, kit, or composition of any one of claims 7 to 85, wherein the third binding region binding to EpCAM comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3 sequences, wherein the HCDR1, HCDR2, and HCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 2, 3, and 4, respectively.

87. The combination of any one of claims 1 and 8 to 86, the combination for use of any one of claims 2 and 8 to 86, the method of any one of claims 3 and 8 to 86, the binding agent for use of any one of claims 4, 5 and 8 to 86, the first and second binding agents for use of any one of claims 6 and 8 to 86, or the medical preparation, combination, kit, or composition of any one of claims 76 to 86, wherein the third binding region binding to EpCAM comprises a light chain variable region (VL) comprising a LCDR3 sequence comprising the sequence as set forth in SEQ ID NO: 8.

88. The combination of any one of claims 1 and 8 to 87, the combination for use of any one of claims 2 and 8 to 87, the method of any one of claims 3 and 8 to 87, the binding agent for use of any one of claims 4, 5 and 8 to 87, the first and second binding agents for use of any one of claims 6 and 8 to 87, or the medical preparation, combination, kit, or composition of any one of claims 7 to 87, wherein the third binding region binding to EpCAM comprises a light chain variable region (VL) comprising a LCDR2 sequence comprising the sequence as set forth in SEQ ID NO: 7.

89. The combination of any one of claims 1 and 8 to 88, the combination for use of any one of claims 2 and 8 to 88, the method of any one of claims 3 and 8 to 88, the binding agent for use of any one of claims 4, 5 and 8 to 88, the first and second binding agents for use of any one of claims 6 and 8 to 88, or the medical preparation, combination, kit, or composition of any one of claims 7 to 88, wherein the third binding region binding to EpCAM comprises a light chain variable region (VL) comprising a LCDR1 sequence comprising the sequence as set forth in SEQ ID NO: 6.

90. The combination of any one of claims 1 and 8 to 89, the combination for use of any one of claims 2 and 8 to 89, the method of any one of claims 3 and 8 to 89, the binding agent for use of any one of claims 4, 5 and 8 to 89, the first and second binding agents for use of any one of claims 6 and 8 to 89, or the medical preparation, combination, kit, or composition of any one of claims 7 to 89, wherein the third binding region binding to EpCAM comprises a light chain variable region (VL) comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the LCDR1, LCDR2 and LCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 6, 7, and 8, respectively.

91. The combination of any one of claims 1 and 8 to 90, the combination for use of any one of claims 2 and 8 to 90, the method of any one of claims 3 and 8 to 90, the binding agent for use of any one of claims 4, 5 and 8 to 90, the first and second binding agents for use of any one of claims 6 and 8 to 90, or the medical preparation, combination, kit, or composition of any one of claims 7 to 90, wherein the third binding region binding to EpCAM comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3 sequences and a light chain variable region (VL) comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the HCDR1, HCDR2, and HCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 2, 3, and 4, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 6, 7, and 8, respectively.

92. The combination of any one of claims 1 and 8 to 91, the combination for use of any one of claims 2 and 8 to 91, the method of any one of claims 3 and 8 to 91, the binding agent for use of any one of claims 4, 5 and 8 to 91, the first and second binding agents for use of any one of claims 6 and 8 to 91, or the medical preparation, combination, kit, or composition of any one of claims 7 to 91, wherein the third binding region binding to EpCAM comprises a heavy chain variable region (VH) comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity to the sequence as set forth in SEQ ID NO: 1.

93. The combination of any one of claims 1 and 8 to 92, the combination for use of any one of claims 2 and 8 to 92, the method of any one of claims 3 and 8 to 92, the binding agent for use of any one of claims 4, 5 and 8 to 92, the first and second binding agents for use of any one of claims 6 and 8 to 92, or the medical preparation, combination, kit, or composition of any one of claims 7 to 92, wherein the third binding region binding to EpCAM comprises a heavy chain variable region (VH) comprising the sequence as set forth in SEQ ID NO: 1.

94. The combination of any one of claims 1 and 8 to 93, the combination for use of any one of claims 2 and 8 to 93, the method of any one of claims 3 and 8 to 93, the binding agent for use of any one of claims 4, 5 and 8 to 93, the first and second binding agents for use of any one of claims 6 and 8 to 93, or the medical preparation, combination, kit, or composition of any one of claims 7 to 93, wherein the third binding region binding to EpCAM comprises a light chain variable region (VL) comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity to the sequence as set forth in SEQ ID NO: 5.

95. The combination of any one of claims 1 and 8 to 94, the combination for use of any one of claims 2 and 8 to 94, the method of any one of claims 3 and 8 to 94, the binding agent for use of any one of claims 4, 5 and 8 to 94, the first and second binding agents for use of any one of claims 6 and 8 to 94, or the medical preparation, combination, kit, or composition of any one of claims 7 to 94, wherein the third binding region binding to EpCAM comprises a light chain variable region (VL) comprising the sequence as set forth in SEQ ID NO: 5.

96. The combination of any one of claims 1 and 8 to 95, the combination for use of any one of claims 2 and 8 to 95, the method of any one of claims 3 and 8 to 95, the binding agent for use of any one of claims 4, 5 and 8 to 95, the first and second binding agents for use of any one of claims 6 and 8 to 95, or the medical preparation, combination, kit, or composition of any one of claims 7 to 95, wherein the third binding region binding to EpCAM comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the sequence as set forth in SEQ ID NO: 1 and the VL comprises the sequence as set forth in SEQ ID NO: 5.

97. The combination of any one of claims 1 and 8 to 96, the combination for use of any one of claims 2 and 8 to 96, the method of any one of claims 3 and 8 to 96, the binding agent for use of any one of claims 4, 5 and 8 to 96, the first and second binding agents for use of any one of claims 6 and 8 to 96, or the medical preparation, combination, kit, or composition of any one of claims 7 to 96, wherein the third binding region binding to EpCAM comprises heavy and light chain variable regions of an antibody which competes for EpCAM binding with and / or has the specificity for EpCAM of an antibody comprising a heavy chain variable region (VH) and / or a light chain variable region (VL) as set forth in any one of claims 83 to 96.

98. The combination of any one of claims 1 and 8 to 97, the combination for use of any one of claims 2 and 8 to 97, the method of any one of claims 3 and 8 to 97, the binding agent for use of any one of claims 4, 5 and 8 to 97, the first and second binding agents for use of any one of claims 6 and 8 to 97, or the medical preparation, combination, kit, or composition of any one of claims 7 to 97, wherein the third binding region binding to EpCAM comprises a single-chain fragment (e.g., scFv) or a VHH.

99. The combination of any one of claims 1 and 8 to 98, the combination for use of any one of claims 2 and 8 to 98, the method of any one of claims 3 and 8 to 98, the binding agent for use of any one of claims 4, 5 and 8 to 98, the first and second binding agents for use of any one of claims 6 and 8 to 98, or the medical preparation, combination, kit, or composition of any one of claims 7 to 98, wherein the fourth binding region which binds to 4-1BB and which agonizes 4-1BB activity comprises an anti-4-1BBE antibody or an 4-1BB binding fragment thereof.

100. The combination of any one of claims 1 and 8 to 99, the combination for use of any one of claims 2 and 8 to 99, the method of any one of claims 3 and 8 to 99, the binding agent for use of any one of claims 4, 5 and 8 to 99, the first and second binding agents for use of any one of claims 6 and 8 to 99, or the medical preparation, combination, kit, or composition of any one of claims 7 to 99,wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a heavy chain variable region (VH) comprising a HCDR3 sequence comprising the sequence as set forth in SEQ ID NO: 14.

101. The combination of any one of claims 1 and 8 to 100, the combination for use of any one of claims 2 and 8 to 100, the method of any one of claims 3 and 8 to 100, the binding agent for use of any one of claims 4, 5 and 8 to 100, the first and second binding agents for use of any one of claims 6 and 8 to 100, or the medical preparation, combination, kit, or composition of any one of claims 7 to 100, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a heavy chain variable region (VH) comprising a HCDR2 sequence comprising the sequence as set forth in SEQ ID NO: 13.

102. The combination of any one of claims 1 and 8 to 101 the combination for use of any one of claims 2 and 8 to 101, the method of any one of claims 3 and 8 to 101, the binding agent for use of any one of claims 4, 5 and 8 to 101, the first and second binding agents for use of any one of claims 6 and 8 to 101, or the medical preparation, combination, kit, or composition of any one of claims 7 to 101, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a heavy chain variable region (VH) comprising a HCDR1 sequence comprising the sequence as set forth in SEQ ID NO: 12.

103. The combination of any one of claims 1 and 8 to 102, the combination for use of any one of claims 2 and 8 to 102, the method of any one of claims 3 and 8 to 102, the binding agent for use of any one of claims 4, 5 and 8 to 102, the first and second binding agents for use of any one of claims 6 and 8 to 102, or the medical preparation, combination, kit, or composition of any one of claims 7 to 102, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3 sequences, wherein the HCDR1, HCDR2, and HCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 12, 13, and 14, respectively.

104. The combination of any one of claims 1 and 8 to 103, the combination for use of any one of claims 2 and 8 to 103, the method of any one of claims 3 and 8 to 103, the binding agent for use of any one of claims 4, 5 and 8 to 103, the first and second binding agents for use of any one of claims 6 and 8 to 103, or the medical preparation, combination, kit, or composition of any one of claims 7 to 103, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a light chain variable region (VL) comprising a LCDR3 sequence comprising the sequence as set forth in SEQ ID NO: 18.

105. The combination of any one of claims 1 and 8 to 104, the combination for use of any one of claims 2 and 8 to 104, the method of any one of claims 3 and 8 to 104, the binding agent for use of any one of claims 4, 5 and 8 to 104, the first and second binding agents for use of any one of claims 6 and 8 to 104, or the medical preparation, combination, kit, or composition of any one of claims 7 to 104, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises alight chain variable region (VL) comprising a LCDR2 sequence comprising the sequence as set forth in SEQ ID NO: 17.

106. The combination of any one of claims 1 and 8 to 105, the combination for use of any one of claims 2 and 8 to 105, the method of any one of claims 3 and 8 to 105, the binding agent for use of any one of claims 4, 5 and 8 to 105, the first and second binding agents for use of any one of claims 6 and 8 to 105, or the medical preparation, combination, kit, or composition of any one of claims 7 to 105, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a light chain variable region (VL) comprising a LCDR1 sequence comprising the sequence as set forth in SEQ ID NO: 16.

107. The combination of any one of claims 1 and 8 to 106, the combination for use of any one of claims 2 and 8 to 106, the method of any one of claims 3 and 8 to 106, the binding agent for use of any one of claims 4, 5 and 8 to 106, the first and second binding agents for use of any one of claims 6 and 8 to 106, or the medical preparation, combination, kit, or composition of any one of claims 7 to 106, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a light chain variable region (VL) comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the LCDR1, LCDR2, and LCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 16, 17 and 18, respectively.

108. The combination of any one of claims 1 and 8 to 107, the combination for use of any one of claims 2 and 8 to 107, the method of any one of claims 3 and 8 to 107, the binding agent for use of any one of claims 4, 5 and 8 to 107, the first and second binding agents for use of any one of claims 6 and 8 to 107, or the medical preparation, combination, kit, or composition of any one of claims 7 to 107, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3 sequences and a light chain variable region (VL) comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the HCDR1, HCDR2, and HCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 12, 13, and 14, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprises the sequences as set forth in SEQ ID NO: 16, 17 and 18, respectively.

109. The combination of any one of claims 1 and 8 to 108, the combination for use of any one of claims 2 and 8 to 108, the method of any one of claims 3 and 8 to 108, the binding agent for use of any one of claims 4, 5 and 8 to 108, the first and second binding agents for use of any one of claims 6 and 8 to 108, or the medical preparation, combination, kit, or composition of any one of claims 7 to 108, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a heavy chain variable region (VH) comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity to the sequence as set forth in SEQ ID NO: 11.

110. The combination of any one of claims 1 and 8 to 109, the combination for use of any one of claims 2 and 8 to 109, the method of any one of claims 3 and 8 to 109, the binding agent for use ofany one of claims 4, 5 and 8 to 109, the first and second binding agents for use of any one of claims 6 and 8 to 109, or the medical preparation, combination, kit, or composition of any one of claims 7 to 109, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a heavy chain variable region (VH) comprising the sequence as set forth in SEQ ID NO: 11.

111. The combination of any one of claims 1 and 8 to 110, the combination for use of any one of claims 2 and 8 to 110, the method of any one of claims 3 and 8 to 110, the binding agent for use of any one of claims 4, 5 and 8 to 110, the first and second binding agents for use of any one of claims 6 and 8 to 110, or the medical preparation, combination, kit, or composition of any one of claims 7 to 110, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a light chain variable region (VL) comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% identity to the sequence as set forth in SEQ ID NO: 15.

112. The combination of any one of claims 1 and 8 to 111, the combination for use of any one of claims 2 and 8 to 111, the method of any one of claims 3 and 8 to 111, the binding agent for use of any one of claims 4, 5 and 8 to 111, the first and second binding agents for use of any one of claims 6 and 8 to 111, or the medical preparation, combination, kit, or composition of any one of claims 7 to 111, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a light chain variable region (VL) comprising the sequence as set forth in SEQ ID NO: 15.

113. The combination of any one of claims 1 and 8 to 112, the combination for use of any one of claims 2 and 8 to 112, the method of any one of claims 3 and 8 to 112, the binding agent for use of any one of claims 4, 5 and 8 to 112, the first and second binding agents for use of any one of claims 6 and 8 to 112, or the medical preparation, combination, kit, or composition of any one of claims 7 to 112, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the sequence as set forth in SEQ ID NO: 11 and the VL comprises the sequence as set forth in SEQ ID NO: 15.

114. The combination of any one of claims 1 and 8 to 113, the combination for use of any one of claims 2 and 8 to 113, the method of any one of claims 3 and 8 to 113, the binding agent for use of any one of claims 4, 5 and 8 to 113, the first and second binding agents for use of any one of claims 6 and 8 to 113, or the medical preparation, combination, kit, or composition of any one of claims 7 to 113, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises heavy and light chain variable regions of an antibody which competes for 4-1BB binding with and / or has the specificity for 4-1BB of an antibody comprising a heavy chain variable region and / or a light chain variable region as set forth in any one of claims 99 to 113.

115. The combination of any one of claims 1 and 8 to 114, the combination for use of any one of claims 2 and 8 to 114, the method of any one of claims 3 and 8 to 114, the binding agent for use of any one of claims 4, 5 and 8 to 114, the first and second binding agents for use of any one of claims 6and 8 to 114, or the medical preparation, combination, kit, or composition of any one of claims 7 to 114, whereina) the third binding region binding to EpCAM comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3 sequences and a light chain variable region (VL) comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the HCDR1, HCDR2, and HCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 2, 3, and 4, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 6, 7, and 8, respectively; and b) the fourth binding region binding to 4-1BB comprises a heavy chain variable region (VH) comprising HCDR1, HCDR2, and HCDR3 sequences and a light chain variable region (VL) comprising LCDR1, LCDR2, and LCDR3 sequences, wherein the HCDR1, HCDR2, and HCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 12, 13, and 14, respectively, and the LCDR1, LCDR2, and LCDR3 sequences comprises the sequences as set forth in SEQ ID NO: 16, 17 and 18, respectively.

116. The combination of any one of claims 1 and 8 to 115, the combination for use of any one of claims 2 and 8 to 115, the method of any one of claims 3 and 8 to 115, the binding agent for use of any one of claims 4, 5 and 8 to 115, the first and second binding agents for use of any one of claims 6 and 8 to 115, or the medical preparation, combination, kit, or composition of any one of claims 7 to 115, wherein the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity comprises a single-chain fragment (e.g., scFv) or a VHH.

117. The combination of any one of claims 1 and 8 to 116, the combination for use of any one of claims 2 and 8 to 116, the method of any one of claims 3 and 8 to 116, the binding agent for use of any one of claims 4, 5 and 8 to 116, the first and second binding agents for use of any one of claims 6 and 8 to 116, or the medical preparation, combination, kit, or composition of any one of claims 7 to 116,wherein the first binding agent does not comprise a binding region binding to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction other than the first binding region and does not comprise a binding region binding to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction other than the second binding region; and / orwherein the second binding agent does not comprise a binding region which binds to EpCAM other than the third binding region and does not comprise a binding region binding to 4-1BB and which agonizes 4-1BB activity other than the fourth binding region.

118. The combination of any one of claims 1 and 8 to 117, the combination for use of any one of claims 2 and 8 to 117, the method of any one of claims 3 and 8 to 117, the binding agent for use of any one of claims 4, 5 and 8 to 117, the first and second binding agents for use of any one of claims 6 and 8 to 117, or the medical preparation, combination, kit, or composition of any one of claims 7 to 117, wherein the second binding agent is an antibody comprising a first binding arm comprising thethird binding region binding to EpCAM and a second binding arm comprising the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity, whereinthe first binding arm comprisesi) a polypeptide comprising a first heavy chain variable region (VH) and a first heavy chain constant region (CH), andii) a polypeptide comprising a first light chain variable region (VL) and a first light chain constant region (CL);and the second binding arm comprisesiii) a polypeptide comprising a second heavy chain variable region (VH) and a second heavy chain constant region (CH), andiv) a polypeptide comprising a second light chain variable region (VL) and a second light chain constant region (CL).

119. The combination of claim 118, the combination for use of claim 118, the method of claim 118, the binding agent for use of claim 118, the first and second binding agents for use of claim 118, or the medical preparation, combination, kit, or composition of claim 118, whereinthe first VH comprises first HCDR.1, HCDR2, and HCDR3 sequences and the first VL comprises first LCDR.1, LCDR2, and LCDR3 sequences, wherein the first HCDR1, HCDR2, and HCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 2, 3, and 4, respectively, and the first LCDR1, LCDR2, and LCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 6, 7, and 8, respectively; andthe second VH comprises second HCDR1, HCDR2, and HCDR3 sequences and the second VL comprises second LCDR1, LCDR2, and LCDR3 sequences, wherein the second HCDR1, HCDR2, and HCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 12, 13, and 14, respectively, and the second LCDR1, LCDR2, and LCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 16, 17, and 18, respectively.

120. The combination of claim 118 or 119, the combination for use of claim 118 or 119, the method of claim 118 or 119, the binding agent for use of claim 118 or 119, the first and second binding agents for use of claim 118 or 119, or the medical preparation, combination, kit, or composition of claim 118 or 119, whereinthe first VH comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to the amino acid sequence as set forth in SEQ ID NO: 1 and the first VL comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to the amino acid sequence as set forth in SEQ ID NO: 5; andthe second VH comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to the amino acid sequence as set forth in SEQ ID NO: 11 and the second VL comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to the amino acid sequence as set forth in SEQ ID NO: 15.

121. The combination of any one of claims 118 to 120, the combination for use of any one of claims 118 to 120, the method of any one of claims 118 to 120, the binding agent for use of any one of claims 118 to 120, the first and second binding agents for use of any one of claims 118 to 120, or the medical preparation, combination, kit, or composition of any one of claims 118 to 120, whereinthe first VH comprises the amino acid sequence as set forth in SEQ ID NO: 1 and the first VL comprises the amino acid sequence as set forth in SEQ ID NO: 5; andthe second VH comprises the amino acid sequence as set forth in SEQ ID NO: 11 and the second VL comprises the amino acid sequence as set forth in SEQ ID NO: 15.

122. The combination of any one of claims 118 to 121, the combination for use of any one of claims 118 to 121, the method of any one of claims 118 to 121, the binding agent for use of any one of claims 118 to 121, the first and second binding agents for use of any one of claims 118 to 121, or the medical preparation, combination, kit, or composition of any one of claims 118 to 121, wherein each of the first and second heavy chain constant regions (CHs) comprises one or more of a constant heavy chain 1 (CHI) region, a hinge region, a constant heavy chain 2 (CH2) region and a constant heavy chain 3 (CH3) region, preferably at least a hinge region, a CH2 region and a CH3 region.

123. The combination of any one of claims 118 to 122, the combination for use of any one of claims 118 to 122, the method of any one of claims 118 to 122, the binding agent for use of any one of claims 118 to 122, the first and second binding agents for use of any one of claims 118 to 122, or the medical preparation, combination, kit, or composition of any one of claims 118 to 122, wherein each of the first and second heavy chain constant regions (CHs) comprises a CH3 region and wherein the two CH3 regions comprise asymmetrical mutations.

124. The combination of any one of claims 118 to 123, the combination for use of any one of claims 118 to 123, the method of any one of claims 118 to 123, the binding agent for use of any one of claims 118 to 123, the first and second binding agents for use of any one of claims 118 to 123, or the medical preparation, combination, kit, or composition of any one of claims 118 to 123, wherein (i) the amino acid in the position corresponding to F405 in a human IgGl heavy chain according to EU numbering is L in said first heavy chain constant region (CH), and the amino acid in the position corresponding to K409 in a human IgGl heavy chain according to EU numbering is R in said second heavy chain constant region (CH), or (ii) the amino acid in the position corresponding to K409 in a human IgGl heavy chain according to EU numbering is R in said first heavy chain constant region (CH), and the amino acid inthe position corresponding to F405 in a human IgGl heavy chain according to EU numbering is L in said second heavy chain constant region (CH).

125. The combination of any one of claims 118 to 124, the combination for use of any one of claims 118 to 124, the method of any one of claims 118 to 124, the binding agent for use of any one of claims 118 to 124, the first and second binding agents for use of any one of claims 118 to 124, or the medical preparation, combination, kit, or composition of any one of claims 118 to 124, wherein said binding agent induces Fc-mediated effector function to a lesser extent compared to another antibody comprising the same first and second antigen binding regions and two heavy chain constant regions (CHs) comprising human IgGl hinge, CH2 and CH3 regions.

126. The combination of any one of claims 118 to 125, the combination for use of any one of claims 118 to 125, the method of any one of claims 118 to 125, the binding agent for use of any one of claims 118 to 125, the first and second binding agents for use of any one of claims 118 to 125, or the medical preparation, combination, kit, or composition of any one of claims 118 to 125, wherein said first and second heavy chain constant regions (CHs) are modified so that the antibody induces Fc-mediated effector function to a lesser extent compared to an antibody which is identical except for comprising non-modified first and second heavy chain constant regions (CHs).

127. The combination of any one of claims 118 to 126, the combination for use of any one of claims 118 to 126, the method of any one of claims 118 to 126, the binding agent for use of any one of claims 118 to 126, the first and second binding agents for use of any one of claims 118 to 126, or the medical preparation, combination, kit, or composition of any one of claims 118 to 126, wherein in at least one of said first and second heavy chain constant regions (CHs), one or more amino acids in the positions corresponding to positions L234, L235, D265, N297, P331, and G236 in a human IgGl heavy chain according to EU numbering, are not L, L, D, N, P, and G, respectively.

128. The combination of claim 127, the combination for use of claim 127, the method of claim 127, the binding agent for use of claim 127, the first and second binding agents for use of claim 127, or the medical preparation, combination, kit, or composition of claim 127, wherein the positions corresponding to positions L234 and L235 in a human IgGl heavy chain according to EU numbering are F and E, respectively, in said first and second heavy chains.

129. The combination of claim 127 or 128, the combination for use of claim 127 or 128, the method of claim 127 or 128, the binding agent for use of claim 127 or 128, the first and second binding agents for use of claim 127 or 128, or the medical preparation, combination, kit, or composition of claim 127 or 128, wherein the positions corresponding to positions L234, L235, and D265 in a human IgGl heavy chain according to EU numbering are F, E, and A, respectively, in said first and / or second heavy chain constant regions (HCs) and / or the positions corresponding to positions L234, L235, and G236 in a human IgGl heavy chain according to EU numbering are F, E, and R, respectively, in said first and / or second heavy chain constant regions (HCs).

130. The combination of any one of claims 127 to 129, the combination for use of any one of claims 127 to 129, the method of any one of claims 127 to 129, the binding agent for use of any one of claims 127 to 129, the first and second binding agents for use of any one of claims 127 to 129, or the medical preparation, combination, kit, or composition of any one of claims 127 to 129, wherein(i) the positions corresponding to positions L234, L235, and D265 in a human IgGl heavy chain according to EU numbering are F, E, and A, respectively, in both said first and second heavy chain constant regions;(ii) the positions corresponding to positions L234, L235, and G236 in a human IgGl heavy chain according to EU numbering are F, E, and R, respectively, in both said first and second heavy chain constant regions; or(iii) the positions corresponding to positions L234, L235, and D265 in a human IgGl heavy chain according to EU numbering are F, E, and A, respectively, in one of said first and second heavy chain constant regions and the positions corresponding to positions L234, L235, and G236 in a human IgGl heavy chain according to EU numbering are F, E, and R, respectively, in the other of said first and second heavy chain constant regions.

131. The combination of any one of claims 127 to 130, the combination for use of any one of claims 127 to 130, the method of any one of claims 127 to 130, the binding agent for use of any one of claims 127 to 130, the first and second binding agents for use of any one of claims 127 to 130, or the medical preparation, combination, kit, or composition of any one of claims 127 to 130, wherein the positions corresponding to positions L234 and L235 in a human IgGl heavy chain according to EU numbering of both the first and second heavy chain constant regions are F and E, respectively, and wherein (i) the position corresponding to F405 in a human IgGl heavy chain according to EU numbering of the first heavy chain constant region is L, and the position corresponding to K409 in a human IgGl heavy chain according to EU numbering of the second heavy chain constant region is R, or (ii) the position corresponding to K409 in a human IgGl heavy chain according to EU numbering of the first heavy chain constant region is R, and the position corresponding to F405 in a human IgGl heavy chain according to EU numbering of the second heavy chain constant region is L.

132. The combination of any one of claims 127 to 131, the combination for use of any one of claims 127 to 131, the method of any one of claims 127 to 131, the binding agent for use of any one of claims 127 to 131, the first and second binding agents for use of any one of claims 127 to 131, or the medical preparation, combination, kit, or composition of any one of claims 127 to 131, wherein the positions corresponding to positions L234, L235, and D265 in a human IgGl heavy chain according to EU numbering are F, E, and A, respectively, in said second heavy chain constant region (HC) and the positions corresponding to positions L234, L235, and G236 in a human IgGl heavy chain according to EU numbering are F, E, and R, respectively, in said first heavy chain constant region (HC), and wherein (i) the position corresponding to F405 in a human IgGl heavy chain according to EU numbering of the first heavy chain constant region is L, and the position corresponding to K409 in a human IgGl heavychain according to EU numbering of the second heavy chain constant region is R, or (ii) the position corresponding to K409 in a human IgGl heavy chain according to EU numbering of the first heavy chain constant region is R, and the position corresponding to F405 in a human IgGl heavy chain according to EU numbering of the second heavy chain constant region is L.

133. The combination of any one of claims 127 to 132, the combination for use of any one of claims 127 to 132, the method of any one of claims 127 to 132, the binding agent for use of any one of claims 127 to 132, the first and second binding agents for use of any one of claims 127 to 132, or the medical preparation, combination, kit, or composition of any one of claims 127 to 132, wherein the positions corresponding to positions L234, L235, and D265 in a human IgGl heavy chain according to EU numbering are F, E, and A, respectively, in said second heavy chain constant region (HC) and the positions corresponding to positions L234, L235, and G236 in a human IgGl heavy chain according to EU numbering are F, E, and R, respectively, in said first heavy chain constant region (HC), and wherein the position corresponding to F405 in a human IgGl heavy chain according to EU numbering of the first heavy chain constant region is L, and the position corresponding to K409 in a human IgGl heavy chain according to EU numbering of the second heavy chain constant region is R.

134. The combination of any one of claims 118 to 133, the combination for use of any one of claims 118 to 133, the method of any one of claims 118 to 133, the binding agent for use of any one of claims 118 to 133, the first and second binding agents for use of any one of claims 118 to 133, or the medical preparation, combination, kit, or composition of any one of claims 118 to 133, whereina) the constant region of said first heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 54; andb) the constant region of said second heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 52.

135. The combination of any one of claims 1 and 8 to 134, the combination for use of any one of claims 2 and 8 to 134, the method of any one of claims 3 and 8 to 134, the binding agent for use of any one of claims 4, 5 and 8 to 134, the first and second binding agents for use of any one of claims 6 and 8 to 134, or the medical preparation, combination, kit, or composition of any one of claims 7 to 134, wherein the second binding agent is an antibody comprising a first binding arm comprising the third binding region binding to EpCAM and a second binding arm comprising the fourth binding region binding to 4-1BB and which agonizes 4-1BB activity, whereinthe first binding arm comprises:i) a polypeptide comprising a first heavy chain variable region (VH) and a first heavy chain constant region (CH), andii) a polypeptide comprising a first light chain variable region (VL) and a first light chain constant region (CL),wherein the first VH comprises first HCDR1, HCDR2, and HCDR3 sequences and the first VL comprises first LCDR1, LCDR2, and LCDR3 sequences, wherein the first HCDR1, HCDR2, and HCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 2, 3, and 4, respectively, and the first LCDR1, LCDR2, and LCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 6, 7, and 8, respectively;and the second binding arm comprises:iii) a polypeptide comprising a second heavy chain variable region (VH) and a second heavy chain constant region (CH), andiv) a polypeptide comprising a second light chain variable region (VL) and a second light chain constant region (CL),wherein the second VH comprises second HCDR1, HCDR2, and HCDR3 sequences and the second VL comprises second LCDR1, LCDR2, and LCDR3 sequences, wherein the second HCDR1, HCDR2, and HCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 12, 13, and 14, respectively, and the second LCDR1, LCDR2, and LCDR3 sequences comprise the sequences as set forth in SEQ ID NO: 16, 17, and 18, respectively;wherein positions L234, L235, and G236 in a human IgGl heavy chain according to EU numbering are F, E, and R, respectively, in the first CH and positions L234, L235, and D265 in a human IgGl heavy chain according to EU numbering are F, E, and A in the second CH; andwherein the amino acid in the position corresponding to F405 in a human IgGl heavy chain according to EU numbering is L in the first CH and the amino acid in the position corresponding to K409 in a human IgGl heavy chain according to EU numbering is R in the second CH.

136. The combination of any one of claims 1 and 8 to 135, the combination for use of any one of claims 2 and 8 to 135, the method of any one of claims 3 and 8 to 135, the binding agent for use of any one of claims 4, 5 and 8 to 135, the first and second binding agents for use of any one of claims 6 and 8 to 135, or the medical preparation, combination, kit, or composition of any one of claims 7 to 135, wherein the second binding agent comprises:i) a first heavy chain comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 9,ii) a first light chain comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 10,iii) a second heavy chain comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 19; andiv) a second light chain comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 20.

137. The combination of any one of claims 1 and 8 to 136, the combination for use of any one of claims 2 and 8 to 136, the method of any one of claims 3 and 8 to 136, the binding agent for use of any one of claims 4, 5 and 8 to 136, the first and second binding agents for use of any one of claims 6 and 8 to 136, or the medical preparation, combination, kit, or composition of any one of claims 7 to 136, wherein the second binding agent comprises:i) a first heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9, ii) a first light chain comprising the amino acid sequence set forth in SEQ ID NO: 10, iii) a second heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 19; and iv) a second light chain comprising the amino acid sequence set forth in SEQ ID NO: 20.

138. The combination of any one of claims 1 and 8 to 137, the combination for use of any one of claims 2 and 8 to 137, the method of any one of claims 3 and 8 to 137, the binding agent for use of any one of claims 4, 5 and 8 to 137, the first and second binding agents for use of any one of claims 6 and 8 to 137, or the medical preparation, combination, kit, or composition of any one of claims 7 to 137, wherein the first binding agent and / or the second binding agent is formulated for injection or infusion.

139. The combination of any one of claims 1 and 8 to 138, the combination for use of any one of claims 2 and 8 to 138, the method of any one of claims 3 and 8 to 138, the binding agent for use of any one of claims 4, 5 and 8 to 138, the first and second binding agents for use of any one of claims 6 and 8 to 138, or the medical preparation, combination, kit, or composition of any one of claims 7 to 138, wherein one or both of the binding agents is / are administered systemically, preferably intravenously.

140. The combination of any one of claims 1 and 8 to 139, the combination for use of any one of claims 2 and 8 to 139, the method of any one of claims 3 and 8 to 139, the binding agent for use of any one of claims 4, 5 and 8 to 139, the first and second binding agents for use of any one of claims 6 and 8 to 139, or the medical preparation, combination, kit, or composition of any one of claims 7 to 139, wherein the first binding agent is to be administered or is administered prior to, simultaneously with, or after administration of the second binding agent.

141. The combination of any one of claims 1 and 8 to 140, the combination for use of any one of claims 2 and 8 to 140, the first and second binding agents for use of any one of claims 6 and 8 to 140, or the medical preparation, combination, kit, or composition of any one of claims 7 to 140, further comprising a further therapeutic agent.

142. The medical preparation, combination, kit, or composition of any one of claims 7 to 141, which comprises a pharmaceutical composition.

143. The medical preparation, combination, kit, or composition of claim 142, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents and / or excipients.

144. The medical preparation, combination, kit, or composition of any one of claims 7 to 143, wherein the medical preparation, combination, kit, or composition is a kit, such as a kit of parts.

145. The medical preparation, combination, kit, or composition of claim 144, wherein the first binding agent and the second binding agent are in separate vials.

146. The medical preparation, combination, kit, or composition of claim 145, wherein the first binding agent in its vial and the second binding agent in its vial are comprised in the same formulation or in a different formulation.

147. The medical preparation, combination, kit, or composition of any one of claims 142 to 146, further comprising instructions for use of the medical preparation or composition for treating or preventing cancer.

148. The combination of any one of claims 1 and 8 to 147 or the medical preparation, combination, kit, or composition of any one of claims 7 to 147 for use as a medicament.

149. The combination for use of claim 148 or the medical preparation, combination, kit, or composition for use of claim 148, wherein the medicament is for administration to a subject.

150. The combination for use of claim 148 or 149 or the medical preparation, combination, kit, or composition for use of claim 148 or 149, wherein the use as a medicament comprises a therapeutic or prophylactic treatment of a disease or disorder.

151. The combination for use of claim 150 or the medical preparation, combination, kit, or composition for use of claim 150, wherein the therapeutic or prophylactic treatment of a disease or disorder comprises treating or preventing cancer.

152. The combination for use of claim 151 or the medical preparation, combination, kit, or composition for use of claim 151, wherein the therapeutic or prophylactic treatment of a disease or disorder further comprises administering radiotherapy, preferably local radiotherapy.

153. The method of any one of claims 3 and 8 to 140, the binding agent for use of any one of claims 4, 5 and 8 to 140, or the first and second binding agents for use of any one of claims 6 and 8 to 140, wherein the method further comprises administering radiotherapy, preferably local radiotherapy, and / or administering a further therapeutic agent.

154. The combination for use of claim 151 or 152, the method of any one of claims 3, 8 to 140, and 153, the binding agent for use of any one of claims 4, 5, 8 to 140, and 153, the first and second bindingagents for use of any one of claims 6 and 8 to 140, or the medical preparation, combination, kit, or composition for use of claim 151 or 152, wherein the cancer is metastatic or advanced malignant solid tumors, metastatic colorectal cancer, or microsatellite stable (MSS)-stable colorectal cancer.

155. The combination for use of any one of claims 149 to 152 and 154, the method of any one of claims 3, 8 to 140, 153, and 154, the binding agent for use of any one of claims 4, 5, 8 to 140, 153, and 154, the first and second binding agents for use of any one of claims 6, 8 to 140, 153 and 154, or the medical preparation, combination, kit, or composition for use of any one of claims 149 to 152 and 154, wherein the subject is a mammal, preferably a human.

156. Use of a first binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction for the manufacture of a medicament for treating or preventing a disease or disorder in a subject in combination with a second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity.

157. Use of a second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity for the manufacture of a medicament for treating or preventing a disease or disorder in a subject in combination with a first binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction.

158. Use of a first binding agent comprising (i) a first binding region which binds to PD-1, PD-L1, or both and which antagonizes the PD-1 / PD-L1 interaction; and (ii) a second binding region which binds to VEGF, VEGF receptor (VEGFR), or both and which antagonizes the VEGF / VEGFR interaction, and a second binding agent comprising (i) a third binding region which binds to EpCAM; and (ii) a fourth binding region which binds to 4-1BB (CD137) and which agonizes 4-1BB activity for the manufacture of a medicament for treating or preventing a disease or disorder in a subject.

159. Use of any one of claims 156 to 158, wherein the disease or disorder is metastatic or advanced malignant solid tumors.

160. Use of claim 159, wherein the disease or disorder is metastatic colorectal cancer.

161. Use of claim 159, wherein the disease or disorder is microsatellite stable (MSS) colorectal cancer.

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