Bispecific Anti-PD-1 x Anti-VEGF-a for the treamtent of metastatic non-small cell lung cancer

Abstract

Provided herein are methods for treating a metastatic non-small cell lung cancer in a subject comprising administering an anti-PD-1 / anti-VEGF-A bispecific antibody to the subject. Also provided are uses of an anti-PD-1 / anti-VEGF-A bispecific antibody for treating a metastatic non-small cell lung cancer in a subject. Also provided are uses of an anti-PD-1 / antiVEGF-A bispecific antibody in the preparation of a medicament for treating a metastatic non-small cell lung cancer in a subject.

Description

[0001] ANTIBODY THERAPY FOR METASTATIC NON-SMALL CELL LUNG CANCER REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (880167_420WO_SEQUENCE_ LISTING.xml; Size: 17,136 bytes; Date of Creation: March 18, 2026) is herein incorporated by reference in its entirety.

[0003] BACKGROUND

[0004] Treatments for metastatic non-small cell lung cancer (mNSCLC) are needed.

[0005] DETAILED DESCRIPTION

[0006] The present disclosure relates, generally, to methods and uses for treating metastatic non-small cell lung cancer (mNSCLC) in a subject ( / .< ., a subject having the metastatic non-small cell lung cancer). Also provided are antibodies and antibody compositions (e.g., pharmaceutical compositions comprising an antibody) for use in the preparation of a medicament for treating metastatic non-small cell lung cancer in a subject. Unless expressly stated otherwise herein, a subject is a human. In some embodiments, a subject is male. In some embodiments, a subject is female. In some embodiments, the metastatic non-small cell lung cancer is a metastatic (Stage IV) lung cancer according to the American Joint Committee on Cancer (AJCC).

[0007] Abbreviations and Definitions

[0008] Prior to setting forth this disclosure in more detail, it may be helpful to an understanding thereof to provide certain abbreviations and additional definitions of certain terms to be used herein. Still more abbreviations and definitions are set forth throughout this disclosure.

[0009] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness, is to be understood to include any integerwithin the recited range, unless otherwise indicated. Any number range recited herein includes the specifically recited value(s) and any integer and non-integer values therebetween, unless otherwise indicated.

[0010] As used herein, the term "about" means ± 20% of the indicated range, value, or structure, unless otherwise indicated. By way of illustration, "about" includes ±15%, ±10%, ±5%, ±3%, and ±1%. The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination of the alternatives. As used herein, the terms "include," "have," and "comprise" are used synonymously, which terms and variants thereof are intended to be construed as non-limiting.

[0011] "Optional" or "optionally" means that the subsequently described element, component, event, or circumstance may or may not occur, and that the description includes instances in which the element, component, event, or circumstance occurs and instances in which they do not.

[0012] In addition, it should be understood that the individual constructs, or groups of constructs, derived from the various combinations of the structures and subunits described herein, are disclosed by the present application to the same extent as if each construct or group of constructs was set forth individually. Thus, selection of particular structures or particular subunits is within the scope of the present disclosure.

[0013] The term "consisting essentially of is not equivalent to "comprising" and refers to the specified materials or steps of a claim, or to those that do not materially affect the basic characteristics of a claimed subject matter.

[0014] The following abbreviations may be used in the disclosure:

[0015] intravenously (IV), as applied to dosing;

[0016] non-small cell lung cancer (NSCLC);

[0017] programmed cell death protein 1 (PD-1);

[0018] programmed cell death ligand 1 (PD-L1);

[0019] vascular endothelial growth factor A (VEGF-A);

[0020] immunohistochemistry (IHC).

[0021] "American Joint Committee on Cancer" and its abbreviation "AJCC" refers to refers to the AJCC’s 8th edition of the Cancer Staging Manual, published by Springer Publishing Company (New York) (2016). An ISBN number of AJCC 8th Edition is 978-3-319-40617-6. The entire contents of AJCC 8th Edition, including the staging systems, descriptions of lungcarcinomas, descriptions of non-small cell lung cancer, and descriptions of metastatic cancer, are incorporated herein by reference. Chapter 36 of AJCC 8th Edition discusses lung carcinomas, including non-small cell and small cell carcinomas, and bronchopulmonary carcinoid tumors and is specifically incorporated herein by reference. Discussion of AJCC 8th Edition is found in, for example, Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT, The 8th Edition Lung Cancer Stage Classification, CHEST (2016), doi: 10.1016 / j.chest.2016.10.010.

[0022] "Common Terminology Criteria for Adverse Events" and its abbreviation "CTCAE" refers to the Common Terminology Criteria for Adverse Events Version 5.0, published by the National Cancer Institute (Maryland) (2017). An ISBN number of the online CTCAE 5th version is 9780191882081. The entire contents of CTCAE 5th Version are incorporated by reference herein. Portions of the CTCAE 5th Version related to any adverse event disclosed herein are specifically incorporated by reference herein. Potential adverse events include: a treatment-emergent adverse event (TEAE), a serious TEAE (TESAE), a treatment-related adverse event (TRAE), or a serious TRAE (TRSAE).

[0023] "Eastern Cooperative Oncology Group performance status" or "ECOG PS" refers to a performance scale published by Eastern Cooperative Oncology Group (now ECOG-ACRIN Cancer Research Group)(Pennsylvania)(1982). The ECOG PS defines six grades (sometimes referred to as stages) of cancer as follows: 0 - Fully active, able to carry on all pre-disease performance without restriction; 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2 - Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours; 3 - Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours; 4 - Completely disabled; cannot carry on any selfcare; totally confined to bed or chair; 5 - Dead.

[0024] "Response Evaluation Criteria in Solid Tumors" or "RECIST" refers to the Response Evaluation Criteria in Solid Tumors, Version 1.1 published by the European Journal of Cancer (United Kingdom) (2009). The entirety of RECIST vl.l is incorporated by reference herein. The portions of RECIST vl.l addressing target lesions or any other tumor discussed herein is specifically incorporated by reference herein.

[0025] "Tumor proportion score" or "TPS" refers to a score calculated based on pathologist analysis of the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, California). TPS is expressed as a percentage in which TPS (%) = [(number of PD-L1 positive tumor cells) / (total number of PD-L1 positive tumor cells + PD-L1 negative tumor cells)] x 100. TPS is commonly used to determine PD-L1 expression in tumor tissue, with a higher TPS reflecting greater PD-L1 expression.

[0026] "SP263 score" refers to a score calculated based on pathologist analysis of the VENTANA® PD-L1 (SP263) assay (Roche Diagnostics, Indiana). SP263 score is expressed a percentage of tumor cells observed with any membrane staining about background levels, often abbreviated as "TC".

[0027] As used herein, "Treat," "treatment," or "ameliorate" refers to medical management of a disease, disorder, or condition of a subject. In general, an appropriate dose or treatment regimen comprising an antibody or a pharmaceutical composition comprising an antibody is administered or is to be administered in an amount sufficient to elicit a therapeutic benefit. Therapeutic benefit includes improved clinical outcome; lessening or alleviation of symptoms associated with cancer; decreased occurrence of symptoms; improved quality of life; longer disease-free status; diminishment of extent of disease, stabilization of cancer state; delay or prevention of disease progression; remission; survival; prolonged survival; or any combination thereof.

[0028] In some embodiments, therapeutic benefit includes extended progression-free survival (“PFS”) and / or extended overall survival "OS") as compared to a reference subject or reference cohort receiving, or that received, no therapy and / or as compared to a reference subject or reference cohort receiving a different therapy (e.g., pembrolizumab), or both. PFS can be assessed per RECIST.

[0029] In some embodiments, therapeutic benefit includes a partial response. In some embodiments, a partial response is a decrease in the size of a tumor or in the amount of the cancer in the body. In some embodiments, a partial response is a decrease in ECOG PS. In some embodiments, therapeutic benefit includes a complete response. A complete response is the disappearance of all signs of the cancer in the body.

[0030] A "therapeutically effective amount" or "effective amount" of an agent of this disclosure refers to an amount of the agent sufficient to result in a therapeutic benefit, such as improved clinical outcome; lessening or alleviation of symptoms associated with a disease; decreased occurrence of symptoms; improved quality of life; longer disease-free status; diminishment of extent of disease, stabilization of disease state; delay of disease progression;remission; survival; partial response; complete response; extended PFS; or extended OS in a statistically significant manner.

[0031] When referring to an individual active ingredient, administered alone, a therapeutically effective amount refers to the effects of that ingredient alone. When referring to a combination, a therapeutically effective amount refers to the combined amounts of active ingredients or combined adjunctive active ingredient that result(s) in a therapeutic effect, whether administered serially, sequentially, concurrently, or simultaneously. A combination may comprise two different active ingredients. A combination of active ingredients can be administered in a series. A combination of active ingredients can be administered sequentially. A combination of active ingredients can be administered simultaneously. A combination of active ingredients can be administered concurrently. A combination of active ingredients can be administered in two or more separate compositions.

[0032] “Administration” or “administer” refers to the act of physically delivering a substance as it exists outside the body (e.g.. an antibody) into a subject. In some embodiments, an antibody or pharmaceutical composition is administered by IV.

[0033] As used herein, "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that function in a manner similar to a naturally occurring amino acid. In some embodiments, all of the amino acids present in a protein in accordance with the present disclosure are naturally occurring amino acids.

[0034] As used herein, "mutation" refers to a change in the sequence of a nucleic acid molecule or polypeptide molecule as compared to a reference or wild-type nucleic acid molecule or polypeptide molecule, respectively. A mutation can result in several differenttypes of change in sequence, including substitution, insertion or deletion of nucleotide(s) or amino acid(s).

[0035] A "conservative substitution" refers to amino acid substitutions that do not significantly affect or alter binding characteristics of a particular protein. Generally, conservative substitutions are ones in which a substituted amino acid residue is replaced with an amino acid residue having a similar side chain. Conservative substitutions include a substitution found in one of the following groups: Group 1 : Alanine (Ala or A), Glycine (Gly or G), Serine (Ser or S), Threonine (Thr or T); Group 2: Aspartic acid (Asp or D), Glutamic acid (Glu or E); Group 3: Asparagine (Asn orN), Glutamine (Gin or Q); Group 4: Arginine (Arg or R), Lysine (Lys or K), Histidine (His or H); Group 5: Isoleucine (He or I), Leucine (Leu or L), Methionine (Met or M), Valine (Vai or V); and Group 6: Phenylalanine (Phe or F), Tyrosine (Tyr or Y), Tryptophan (Trp or W). Additionally, or alternatively, amino acids can be grouped into conservative substitution groups by similar function, chemical structure, or composition (e.g., acidic, basic, aliphatic, aromatic, or sulfur-containing). For example, an aliphatic grouping may include, for purposes of substitution, Gly, Ala, Vai, Leu, and He. Other conservative substitutions groups include: sulfur-containing: Met and Cysteine (Cys or C); acidic: Asp, Glu, Asn, and Gin; small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro, and Gly; polar, negatively charged residues and their amides: Asp, Asn, Glu, and Gin; polar, positively charged residues: His, Arg, and Lys; large aliphatic, nonpolar residues: Met, Leu, He, Vai, and Cys; and large aromatic residues: Phe, Tyr, and Trp.

[0036] Additional information can be found in Creighton (1984) Proteins, W.H. Freeman and Company. Variant proteins, peptides, polypeptides, and amino acid sequences of the present disclosure can, in certain embodiments, comprise one or more conservative substitutions relative to a reference amino acid sequence.

[0037] As used herein, "protein" or "polypeptide" refers to a polymer of amino acid residues. Proteins apply to naturally occurring amino acid polymers, as well as to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid and non-naturally occurring amino acid polymers. Peptides are short proteins, for example from about 5 to about 50 amino acids in length.

[0038] Terms understood by those in the art of antibody technology are each given the meaning acquired in the art, unless expressly defined differently herein. For example, the term “antibody” refers to an intact antibody comprising at least two heavy (H) chains and twolight (L) chains inter-connected by disulfide bonds, as well as any antigen-binding portion or fragment of an intact antibody that has or retains the ability to bind to the antigen target molecule recognized by the intact antibody, such as an scFv, Fab, Fcab, or Fab’2 fragment. Thus, the term “antibody” herein is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments thereof, including fragment antigen binding (Fab) fragments, F(ab’)2 fragments, Fab’ fragments, Fv fragments, recombinant IgG (rlgG) fragments, single chain antibody fragments, including single chain variable fragments (scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, antibodies from a cartilaginous fish or camelid, or a fragment thereof (e.g., IgNAR, VNAR, VHH) and heteroconjugate antibodies, multi specific, e.g., bispecific antibodies, trispecific antibodies, diabodies, triabodies, tetrabodies, IgG-scFv, antibody fusion proteins that comprise at least a fragment of a naturally occurring ligand or receptor (e.g., TGF or TGF R), tandem di-scFv, and tandem tri-scFv. Unless otherwise stated, the term “antibody” should be understood to encompass functional antibody fragments thereof. The term also encompasses intact or full-length antibodies, including antibodies of any class or sub-class, including IgG and subclasses thereof (IgGl, IgG2, IgG3, IgG4), IgM, IgE, IgA, and IgD.

[0039] The terms “VL” or “VL” and “VH” or “VH” refer to the variable binding region (also called variable region or variable binding domain or variable domain) from an antibody light chain and an antibody heavy chain, respectively. In certain embodiments, a VL is a kappa (K) class (also “VK” herein). In certain embodiments, a VL is a lambda (1) class. The variable binding regions comprise discrete, well-defined sub-regions known as “complementarity determining regions” (CDRs) and “framework regions” (FRs). The terms “complementarity determining region,” and “CDR,” are synonymous with “hypervariable region” or “HVR,” and refer to sequences of amino acids within antibody variable regions, which, in general, together confer the antigen specificity and / or binding affinity of the antibody, wherein consecutive CDRs (i.e., CDR1 and CDR2, CDR2 and CDR3) are separated from one another in primary structure by a framework region. There are three CDRs in each variable region (HCDR1, HCDR2, HCDR3; LCDR1, LCDR2, LCDR3; also referred to as CDRHs and CDRLs, respectively). In certain embodiments, an antibody VH comprises four FRs andthree CDRs as follows: FR1-HCDR1-FR2-HCDR2-FR3-HCDR3-FR4; and an antibody VL comprises four FRs and three CDRs as follows: FR1-LCDR1-FR2-LCDR2-FR3-LCDR3-FR4. In general, the VH and the VL together form the antigen-binding site (or domain) through their respective CDRs. In certain embodiments, one or more CDRs do not contact antigen and / or do not contribute energetically to antigen binding (but one or more CDRs do contact antigen).

[0040] As used herein, a “variant” of a CDR refers to a functional variant of a CDR sequence having up to 1-3 amino acid substitutions (e.g., conservative or non-conservative substitutions), deletions, or combinations thereof.

[0041] Numbering of CDR and framework regions may be according to any known method or scheme, such as the Kabat, Chothia, EU, IMGT, Contact, North, Martin, AbM, and Aho numbering schemes (see, e.g., Kabat et al., “Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services, Public Health Service National Institutes of Health, 1991, 5th ed.; Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); Lefranc et al., Dev. Comp. Immunol. 27:55, 2003; Honegger and Pliickthun, J. Mol. Bio. 309:657-670 (2001); North et al. J Mol Biol. (2011) 406:228-56; doi: 10.1016 / j.jmb.2010.10.030; Abhinandan and Martin, Mol Immunol. (2008) 45:3832-9. 10.1016 / j.molimm.2008.05.022). The antibody and CDR numbering systems of these references are incorporated herein by reference.

[0042] Equivalent residue positions can be annotated and for different molecules to be compared using Antigen receptor Numbering And Receptor Classification (ANARCI) software tool (2016, Bioinformatics 15:298-300). Accordingly, identification of CDRs of an exemplary variable domain (VH or VL) sequence as provided herein according to one numbering scheme is not exclusive of an antibody comprising CDRs of the same variable domain as determined using a different numbering scheme. In some embodiments, CDRs are defined in accordance with the IMGT numbering scheme, and CDRH3 and CDRL3 are both defined in accordance with IMGT or IMGT-junction definitions.

[0043] In some embodiments, a method or use of the present disclosure comprises ivonescimab. Ivonescimab is a tetrameric, bispecific antibody targeting human VEGF-A and human PD-1. Ivonescimab comprises an immunoglobulin portion that targets human VEGF-A and an scFv portion (two anti -PD-1 scFvs, each scFv being linked to the C-terminal end of one of the two heavy chains of the immunoglobulin) that targets human PD-1.The heavy chain amino acid sequence of ivonescimab (immunoglobulin heavy chain linked to scFv) is as follows:

[0044] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYT GEPT YAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYC AKYPHYYGS SHWYFD VWGQGTLVTVS S ASTKGPS VFPL APS SKSTSGGTAALGCLVKDYFPEP VT VSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKG GGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWV RQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALY YCANRYGEAWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSM SASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQ DYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKR (SEQ ID NO:1).

[0045] The light chain amino acid sequence of ivonescimab is as follows:

[0046] DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGV PS RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:2).

[0047] The anti-VEGF-AHCDR amino acid sequences of ivonescimab are as follows:

[0048] HCDR1 : GYTFTNYG (SEQ ID NO:3)

[0049] HCDR2: INTYTGEP (SEQ ID NO:4)

[0050] HCDR3: AKYPHYYGS SHWYFD V (SEQ ID NO: 5)

[0051] The anti -VEGF- A heavy chain variable domain amino acid sequence of ivonescimab is as follows:

[0052] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGW INTYTGEPTYAADFKRRFTF SLDTSKSTAYLQMNSLRAEDTAVYYC AKYPHYYGS SH WYFDVWGQGTLVTVSS (SEQ ID NO: 6)

[0053] The anti-VEGF-ALCDR amino acid sequences of ivonescimab are as follows:

[0054] LCDR1 : QDISNY (SEQ ID NO: 7)LCDR2: FTS

[0055] LCDR3: QQYSTVPWT (SEQ ID NO: 8)

[0056] The anti- VEGF -A light chain variable domain amino acid sequence of ivonescimab is:

[0057] DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK (SEQ ID NO: 9)

[0058] The anti-PD-1 scFv (VH-(G4S)41inker-VL orientation) amino acid sequence of ivonescimab is:

[0059] EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATIS GGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSMSASVGDRVTFTCRAS QDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMA TYYCLQYDEFPLTFGAGTKLELKR (SEQ ID NO: 10)

[0060] The anti-PD-1 scFv HCDR amino acid sequences of ivonescimab are as follows: HCDR1: GFAFSSYD (SEQ ID NO: 11)

[0061] HCDR2: ISGGGRYT (SEQ ID NO: 12)

[0062] HCDR3 : ANRYGEAWFAY (SEQ ID NO: 13)

[0063] The anti-PD-1 scFv LCDR amino acid sequences of ivonescimab are as follows: LCDR1 : QDINTY (SEQ ID NO: 14)

[0064] LCDR2: RAN

[0065] LCDR3: LQYDEFPLT (SEQ ID NO: 15)

[0066] Ivonescimab is described in, for example, PCT / CN2020 / 131447 (which published as PCT Publication WO 2021 / 104302), and U.S. Pre-Grant Publication US 2023 / 0027029 Al, the entire contents (including but not limited to the working examples) of which are incorporated herein by reference. Certain embodiments provide methods for treating a disease associated with a tumor in a subject, such as a mNSCLC tumor in a subject (in the CNS or outside of the CNS) wherein the methods comprise an effective amount of a multispecific antibody or antigen-binding fragment thereof comprising one or more VEGF-A binding sites and one or more PD-1 binding sites, wherein the one or more VEGF-A binding site comprises the anti -VEGF A CDR amino acid sequences (CDRH1-CDRH3 and CDRL1-CDRL3, by any recognized CDR numbering scheme or combination of two or more recognized CDRnumbering schemes, and preferably by IMGT) and optionally the anti-VEGFA VH and VL amino acid sequences of ivonescimab, and the one or more PD-1 binding site comprises the anti-PD-1 CDR amino acid sequences (CDRH1-CDRH3 and CDRL1-CDRL3, by any recognized CDR numbering scheme or combination of two or more recognized CDR numbering schemes, and preferably by IMGT) and optionally the anti-PD-1 VH and VL amino acid sequences of ivonescimab, further optionally wherein the multispecific antibody or antigen-binding fragment thereof is a bispecific antibody, still further optionally in IgG-scFv format and / or comprising a modified IgGl Fc domain that comprises one or more mutations that reduce effector function, still further optionally the mutations L234A and L235A. In some embodiments, a method or use of the present disclosure comprises: LM-299 (LaNova Medicines), AL081 (OncoC4), RC148 (Remegen), NY-500 (Naya BioSciences), CR-001 (Crescent Biopharma / GlycoMimentics), CTX-10726 (Compass Therapeutics), JS207 (Junshi), MHB039A(Minghui), SSGJ-707 (Sunshine Guojian), SCTB14 (Sinocelltech), SYN-2510 / IMM2510 (Instil Bio / ImmunOnco), HB0025 (Huabo Biopharma), Jankistomig (Ottimo Pharma), SGI 408 (Zongsheng Shangjian / Sumgen Bio), BB-203 (Bright Biologies), CVL006 (Convalife Pharmaceutical), PM8002 / BNT327 (Biontech / Biotheus), B1962 / AP505 (AP Biosciences), HC010 (HongCheng), PM8003 (Biotheus), GB268 (Genor), CS2009 (CStone Pharmaceuticals), DR30206 (Zhejiang Doer Biologies), or any combination thereof.

[0067] In some embodiments, a method or use of the present disclosure comprises a multispecific molecule as described in any one of the following published PCT applications, patent applications, or patents: WO2024125417; WO2024141027; WO2023134787;

[0068] WO2019154349; US11827697; WO2021244371; WO2024017281; WO2021244371;

[0069] WO2021218684; WO2020114355; W02020200210; W02021069670; WO2024044732; WO2022042719; WO2019168947; WO2024067474; WO2022042719; WO2022174451; CN105175545B; WO2022143801; CN110563849B; WO2024240171; WO2022262832; WO2022174451; WO2022174781; WO2022174452; WO2022111476; and W02025016011.

[0070] In some embodiments, a method or use of the present disclosure comprises a multispecific molecule comprising the CDRs and optionally the variable domain amino acid sequences of a multispecific molecule as described in any one of the following published PCT applications, patent applications, or patents: WO2024125417; WO2024141027;

[0071] WO2023134787; WO2019154349; US11827697; WO2021244371; WO2024017281;WO2021244371; WO2021218684; WO2020114355; W02020200210; W02021069670; WO2024044732; WO2022042719; WO2019168947; WO2024067474; WO2022042719; WO2022174451; CN105175545B; WO2022143801; CN110563849B; WO2024240171; WO2022262832; WO2022174451; WO2022174781; WO2022174452; WO2022111476; and W02025016011.

[0072] “Sequence identity,” as used herein, refers to the percentage of amino acid residues or nucleobases in one sequence that are identical with the amino acid residues or nucleobases (respectively) in a reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. The percentage sequence identity values can be generated using the NCBI BLAST 2.0 software as defined by Altschul et al. (1997), Nucl. Acids Res. 25:3389-3402, with the parameters set to default values.

[0073] Additionally, or alternatively, the degree of sequence identity between two sequences can be determined, for example, by comparing the two sequences using computer programs designed for this purpose, such as global or local alignment algorithms. Non-limiting examples include BLASTp, BLASTn, Clustal W, MAFFT, Clustal Omega, AlignMe, Praline, GAP, BESTFIT, Needle (EMBOSS), Stretcher (EMBOSS), GGEARCH2SEQ, Water (EMBOSS), Matcher (EMBOSS), LALIGN, SSEARCH2SEQ, or another suitable method or algorithm. A global alignment algorithm, such as a Needleman and Wunsch algorithm, can be used to align two sequences over their entire length, maximizing the number of matches and minimizes the number of gaps. Default settings can be used.

[0074] To generate similarity scores for two amino acid sequences, scoring matrices can be used that assign positive scores for some non-identical amino acids (e.g., conservative amino acid substitutions, amino acids with similar physio-chemical properties, and / or amino acids that exhibit frequent substitutions in orthologs, homologs, or paralogs), Non-limiting examples of scoring matrices include PAM30, PAM70, PAM250, BLOSLTM45, BLOSLTM50, BLOUM62, BLOSUM80, and BLOSUM90.

[0075] The present disclosure further includes any of the antibodies disclosed herein, particularly an antibody or combination of antibodies that binds one or more of PD-1, PD-L1, and PD-L2, thereby blocking a PD-l / PD-1 ligand interaction and one or more of VEGFR1, VEGFR2, VEGFR3, VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PIGF, thereby blocking aVEGFR / VEGFR ligand interaction, such as ivonescimab, formulated for use in a non-small cell lung cancer, particularly metastatic non-small cell lung cancer.

[0076] Antibodies for Use in Therapy and Therapeutic Methods

[0077] The present disclosure provides methods of treating non-small cell lung cancer, particularly metastatic non-small cell lung cancer. The present disclosure further provides for the use of any antibody disclosed herein in a medicament for treating any non-small cell lung cancer, particularly metastatic non-small cell lung cancer according to any method disclosed herein.

[0078] Presently disclosed methods comprise administering an antibody (e.g., comprised in a pharmaceutical composition) or a combination of antibodies to a subject. In some embodiments, an antibody that binds VEGF-A and binds PD-1 is a bispecific antibody comprising an IgG-scFv format (see, e.g., (Coloma M. J., Morrison S. L. Design and production of novel tetraval ent bispecific antibodies. Nat Biotechnol., 1997; 15: 159-163)) and binds to human VEGFA and human PD-1. In some embodiments, an antibody that binds PD-1 and binds CTLA4 is a bispecific antibody comprising an IgG-scFv format.

[0079] Terms understood by those in the art of antibody technology are each given the meaning acquired in the art, unless expressly defined differently herein.

[0080] In some embodiments, the subject is administered an antibody (e.g, ivonescimab), or a pharmaceutical composition comprising the antibody, at 1-50 mg / kg of the subject’s body weight, optionally: 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, or 50 mg / kg, and / or every two weeks (Q2W) or every three weeks (Q3W).

[0081] Ivonescimab has been evaluated in clinical settings at 20 mg / kg Q3W and 30 mg / kg Q3W. In some embodiments, the subject is administered an antibody that binds VEGFA and binds PD-1 (e.g, ivonescimab), or a pharmaceutical composition comprising the antibody, at 20 mg / kg or 30 mg / kg of the subject’s body weight, Q2W and / or Q3W.

[0082] In some embodiments, the subject is administered an antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab), or a pharmaceutical composition comprising the antibody, at 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg / kg of the subject’s body weight, optionally Q3W.

[0083] In some embodiments, the subject is administered an antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab), or a pharmaceutical composition comprising the antibody, atabout 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 mg / kg of the subject’s body weight, optionally Q3W.

[0084] In some embodiments, the subject is administered an antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab), or a pharmaceutical composition comprising the antibody, between 20 and 30 mg / kg of the subject’s body weight, optionally Q3W.

[0085] In some embodiments, the subject is administered an antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab), or a pharmaceutical composition comprising the antibody, between about 20 and about 30 mg / kg of the subject’s body weight, optionally Q3W.

[0086] In some embodiments, the subject is administered the antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab) at 20 mg / k Q3W.

[0087] In some embodiments, the subject is administered the antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab) at 30 mg / k Q3W.

[0088] In some embodiments, the subject is administered the antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab) at 20 mg / k Q2W.

[0089] In some embodiments, the subject is administered the antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab) at 30 mg / k Q2W.

[0090] In some embodiments, the antibody that binds VEGFA and binds PD-1 is administered Q3W for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more cycles.

[0091] In some embodiments, a therapy as provided herein provides PFS, e.g., for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, or more.

[0092] In some embodiments, intravenous infusion of the antibody that binds VEGF-A and binds PD-1 (e.g., ivonescimab) occurs over 60 ± 10 minutes, extendable to a maximum of 120± 15 minutes. In some embodiments, intravenous infusion of the antibody that binds VEGF-A and binds PD-1 (e.g., ivonescimab) occurs between 50 minutes and 70 minutes, between 50 minutes and 80 minutes, between 50 minutes and 90 minutes, between 50 minutes and 100 minutes, between 50 minutes and 110 minutes, between 50 minutes and 120 minutes, between 50 minutes and 135 minutes, between 60 minutes and 70 minutes, between 60 minutes and 80 minutes, between 60 minutes and 90 minutes, between 60 minutes and 100 minutes, between 60 minutes and 110 minutes, between 60 minutes and 120 minutes,between 60 minutes and 135 minutes, between 70 minutes and 80 minutes, between 70 minutes and 90 minutes, between 70 minutes and 100 minutes, between 70 minutes and 110 minutes, between 70 minutes and 120 minutes, between 70 minutes and 135 minutes, between 80 minutes and 90 minutes, between 80 minutes and 100 minutes, between 80 minutes and 110 minutes, between 80 minutes and 120 minutes, between 80 minutes and 135 minutes, between 90 minutes and 100 minutes, between 90 minutes and 110 minutes, between 90 minutes and 120 minutes, between 100 minutes and 110 minutes, between 100 minutes and 120 minutes, between 110 minutes and 120 minutes, or between 110 minutes and 135 minutes,.

[0093] In some embodiments, intravenous infusion of the antibody that binds VEGF-A and binds PD-1 (e.g., ivonescimab) occurs over about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 120 minutes, about 130 minutes, or about 135 minutes.

[0094] In some embodiments, a therapy as provided herein provides PFS, e.g., for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, or more.

[0095] In some embodiments, a therapy as provided herein does not result in a treatment-emergent adverse event (TEAE), a serious TEAE (TESAE), a treatment-related adverse event (TRAE), and / or a serious TRAE (TRSAE). Adverse events can be graded according to the CTCAE.

[0096] In some embodiments, the subject who is administered an antibody (e.g., ivonescimab), or a pharmaceutical composition comprising the antibody has not previously received systemic therapy for any metastatic cancer. In some embodiments, the subject has not received systemic therapy for any metastatic cancer for at least 1, 2, or 3 years prior to administration of the antibody or pharmaceutical composition comprising the antibody. In some embodiments, the subject has not previously received systemic therapy for metastatic non-small cell lung cancer. In some embodiments, the subject has previously received systemic therapy for a metastatic cancer, but has demonstrated no evidence of recurrence of the disease for at least three years prior to administration of an antibody or pharmaceutical composition according to the present disclosure.In some embodiments, the subject does not have one or more known actionable genomic alterations associated with cancer risk or progression (also referred to as "activating mutations"), such as the EGFR, ALK, ROS1, and / or BRAF V600E alterations. In some embodiments, the subject does not have any EGFR, ALK, ROS1, and BRAF V600E alterations.

[0097] In some embodiments, the subject has one or more known actionable genomic alterations associated with cancer risk or progression, in particular one or more of the EGFR, ALK, ROS1, and / or BRAF V600E alterations.

[0098] In some embodiments, the subject has high PD-L1 expression in one or more nonsmall cell lung cancer tumors, optionally the primary tumor or a secondary tumor. In some embodiments, high PD-L1 expression in one or more small cell lung cancer tumors is evaluated by immunohistochemical analysis of tumor tissue. In some embodiments, high PD-L1 expression is evidenced by a TPS of greater than or equal to 50% (TPS > 50%). In some embodiments, high PD-L1 expression is evidenced by a SP263 score of greater than or equal to 50% (TC > 50%). In some embodiments, high PD-L1 expression is defined by a score calculated in a different manner that indicates that greater than 50% of tumor cells in an evaluated tumor express PD-L1. In some embodiments, high PD-L1 expression is defined by a score calculated in an automated analysis process that indicates that greater than 50% of tumor cells in an evaluated tumor express PD-L1.

[0099] In some embodiments, the one or more non-small cell lung cancer tumors used to determine PD-L1 expression may be archival (e.g. previously sectioned and stained). In some embodiments, the one or more non-small cell lung cancer tumors used to determine PD-L1 expression may be fresh tumor tissue.

[0100] In some embodiments, the subject has Stage IV mNSCLC according to AJCC guidelines. In some embodiments, the subject has an ECOG PS score of 0 or 1. In some embodiments, the subject has histologically or cytologically confirmed squamous NSCLC. In some embodiments, the subject has histologically or cytologically confirmed nonsquamous NSCLS.

[0101] In some embodiments, subsequent to administration of the antibody that binds VEGFA and binds PD-1 e.g., ivonescimab) the subject exhibits a decrease in ECOG PS score. In some embodiments, the subject exhibits PFS or OS for six months or more, one year or more, or two years or more subsequent to administration of the antibody that bindsVEGFA and binds PD-1 (e.g., ivonescimab). In some embodiments, the subject exhibits PFS or OS for 4 months, 5 months, 6 months, 12 months, 15 months, 18 months, 24 months, 30 months, or 36 months or more subsequent to administration of the antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab).

[0102] In some embodiments, the subject administered the antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab) has not previously received systemic therapy for metastatic non-small cell lung cancer and has one or more tumors with high PD-L1 expression and is administered ivonsecimab at a dose of 20 mg / kg every 3 weeks. According to some embodiments, the subject, subsequent to antibody administration, exhibits a decrease in RECIST score and / or PFS for at least 6 months.

[0103] In some embodiments, the subject administered the antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab) has not previously received systemic therapy for metastatic non-small cell lung cancer and has one or more tumors with high PD-L1 expression and is administered ivonsecimab at a dose of 30 mg / kg every 3 weeks. According to some embodiments, the subject, subsequent to antibody administration, exhibits PFS and / or OS for at least 6 months.

[0104] In some embodiments, the subject administered the antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab) has not previously received systemic therapy for metastatic non-small cell lung cancer and has one or more tumors with high PD-L1 expression and is administered ivonsecimab at a dose of 20 mg / kg every 2 weeks. According to some embodiments, the subject, subsequent to antibody administration, exhibits PFS and / or OS for at least 6 months

[0105] In some embodiments, the subject administered the antibody that binds VEGFA and binds PD-1 (e.g., ivonescimab) has not previously received systemic therapy for metastatic non-small cell lung cancer and has one or more tumors with high PD-L1 expression and is administered ivonsecimab at a dose of 30 mg / kg every 2 weeks. According to some embodiments, the subject, subsequent to antibody administration, exhibits PFS and / or OS for at least 6 months.

[0106] The present disclosure includes the following enumerated Embodiments.

[0107] Embodiment 1. A method for treating a metastatic non-small cell lung cancer in a subject, the method comprising administering to the subject an effective amount of an antibody that binds:one or more of PD-1, PD-L1, and PD-L2, thereby blocking a PD-l / PD-1 ligand interaction; and one or more of VEGFR1, VEGFR2, VEGFR3, VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PIGF, thereby blocking a VEGFR / VEGFR ligand interaction, wherein, optionally, the antibody binds: PD-1 and a VEGF, preferably VEGF-A; PD-L1 and a VEGFR, preferably VEGFR-2 or VEGFR- 1; PD-L1 and a VEGF, preferably VEGF-A; PD-1 and a VEGFR, preferably VEGFR-2 or VEGFR-1; PD-1, CTLA4, and a VEGF; PD-1, TGF0, and a VEGF; or PD-L1, a VEGF, and TGF0.

[0108] Embodiment 2. The method of Embodiment 1, wherein the antibody binds PD- 1 and VEGF-A.

[0109] Embodiment 3. The method of Embodiment 1 or 2, wherein the antibody comprises a VEGF-A-binding domain comprising the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs.3-5 and 7-9, respectively, and a PD-l-binding domain comprising the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs.: 12-14 and 15- 17, respectively.

[0110] Embodiment 4. The method of any one of Embodiments 1-3, wherein the antibody comprises a VEGF-A binding domain comprising the VH amino acid sequence of SEQ ID NO:6 and the VL amino acid sequence of SEQ ID NO:9, and / or wherein the antibody comprises a PD-1 binding domain comprising the VH amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGR YTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGT LVTVSS and the VL amino acid sequence DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSG VPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKR.

[0111] Embodiment 5. The method of any one of Embodiments 1-4, wherein the antibody comprises a tetravalent structure.

[0112] Embodiment 6. The method of any one of Embodiments 1-5, wherein the antibody is in a IgG-scFv format, wherein, optionally, the IgG portion comprises a binding domain that binds one or more of VEGFR1, VEGFR2, VEGFR3, VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PIGF, and wherein the scFv portion comprises two scFvs that each bind one or more of one of PD-1, PD-L1, and PD-L2, wherein, further optionally, the IgG portioncomprises a binding domain that binds to VEGF-A and the scFv portion comprises two scFvs that each bind PD-1.

[0113] Embodiment 7. The method of any one of Embodiments 1-6, wherein the antibody comprises a modified IgGl Fc domain comprising one or more mutations that reduce effector function of the antibody, where, optionally, the one or more mutations comprise the mutations L234A and L235A.

[0114] Embodiment 8. A method for treating a metastatic non-small cell lung cancer in a subject, the method comprising administering to the subject an effective amount of an antibody, wherein the antibody comprises ivonescimab.

[0115] Embodiment 9. The method of any one of Embodiments 1-8, comprising administering to the subject a single dose of the antibody, or of a pharmaceutical composition comprising the antibody, at 20 mg / kg of the subject’s body weight, optionally by intravenous administration and / or once every three weeks.

[0116] Embodiment 10. The method of Embodiment 9, comprising administering to the subject a single dose of the antibody, or of a pharmaceutical composition comprising the antibody, at 20 mg / kg of the subject’s body weight, by intravenous administration, once every three weeks.

[0117] Embodiment 11. The method of any one of Embodiments 1-10, wherein the non-small cell lung cancer has been determined to comprise one or more tumors having PD-L1 expression on at least 50% of tumor cells as determined by immunohistochemical analysis of tumor tissue.

[0118] Embodiment 12. The method of any one of Embodiments 1-11, wherein the non-small cell lung cancer has been determined to comprise one or more tumors having high PD-L1 expression as determined by TPS >50%, based on a PD-L1 22C3 immunohistochemical assay.

[0119] Embodiment 13. The method of any one of Embodiments 1-12, wherein the non-small cell lung cancer has been determined to comprise one or more tumors having a high PD-L1 expression of TC >50%, based on a PD-L1 SP263 immunohistochemical assay.

[0120] Embodiment 14. The method of any one of Embodiments 11-13, wherein the PD-L1 expression is determined from existing immunohistochemical assay results.

[0121] Embodiment 15. The method of any one of Embodiments 11-13, wherein the PD-L1 expression is determined from archival or fresh tumor tissue.Embodiment 16. The method of any one of Embodiments 1-15, wherein the subject has not previously received systemic therapy for metastatic non small cell lung cancer.

[0122] Embodiment 17. The method of any one of Embodiments 1-16, wherein the subject has an ECOG PS score of 0 or 1.

[0123] Embodiment 18. The method of any one of Embodiments 1-17, wherein the subject has a stage IV metastatic non-small cell lung cancer according to American Joint Committee on Cancer (AJCC) guidelines.

[0124] Embodiment 19. The method of any one of Embodiments 1-18, wherein the subject has squamous or nonsquamous non-small cell lung cancer.

[0125] Embodiment 19. The method of any one of Embodiments 1-19, wherein the subject:

[0126] a. is 18 years of age or older;

[0127] b. has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1;

[0128] c. has one or more measurable noncerebral lesion per RECIST vl.l; d. has histologically or cytologically confirmed squamous or non-squamous non-small cell lung cancer;

[0129] e. has not received prior systemic treatment for metastatic non-small cell lung cancer;

[0130] f. has a creatinine clearance (CrCl) > 30 mL / min using the Cockcroft-Gault formula;

[0131] g. has an estimated glomerular filtration rate (eGFR) value > 30 mL / min using the Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) equation;

[0132] h. has urine protein <2+ or 24-hour urine protein quantification <1.0 gram; i. has no known actionable genetic alterations (e.g., no actionable genetic alterations in EGFR, A K, ROS1, or BRAFV600E), optionally for which one or more first-line approved therapy is indicated; and / or

[0133] j. has an expected life expectancy of >3 months.

[0134] Embodiment 20. The method of Embodiment 19, wherein the subject is each of a. to j .Embodiment 21. The method of any one of Embodiments 1-20, wherein the subject, prior to receiving the antibody or a pharmaceutical composition comprising the antibody:

[0135] k. does not have symptomatic CNS metastases, CNS metastasis > 1.5 cm, and / or CNS radiation within 7 days;

[0136] l. is not a candidate for CNS radiation;

[0137] m. does not have leptomeningeal disease;

[0138] n. does not have an autoimmune or lung disease requiring systemic therapy; o. does not have a pre-existing peripheral neuropathy that is > Grade 2 by CTCAE version 5;

[0139] p. does not have a severe infection;

[0140] q. has not had a major surgical procedure or serious trauma within 4 weeks; r. has one or more known actionable genetic alteration (e.g., actionable genetic alteration in EGFR, ALK, ROS1, or BRAFV600E), optionally for which one or more first-line approved therapy is indicated;

[0141] s. does not have a history of noninfectious pneumonia requiring systemic corticosteroids; and / or

[0142] t. does not have lung interstitial disease.

[0143] Embodiment 22. The method of any one of Embodiments 1-21, wherein the subject, prior to receiving the antibody or a pharmaceutical composition comprising the antibody, is each of a. to t.

[0144] Embodiment 23. The method of any one of Embodiments 1-22, wherein the method does not comprise administering an additional non-small cell lung cancer therapeutic agent to the subject.

[0145] Embodiment 24. The method of any one of Embodiments 1-23, wherein subsequent to administering the antibody, the subject experiences: a partial response; a complete response; progression-free survival (PFS), or overall survival (OS) for 4 months, 5 months, 6 months, 12 months, 15 months, 18 months, a 24 months, 30 months, or 36 months or more.

[0146] Embodiment 25. Use of the antibody of any one of Embodiments 1-24 in a method of any one of Embodiments 1-24.EXAMPLES

[0147] EXAMPLE 1: HARMONI-7: A RANDOMIZED PHASE 3 STUDY OF IVONESCIMAB VERSUS PEMBROLIZUMAB AS FIRST-LINE TREATMENT OF METASTATIC NON-SMALL CELL LUNG CANCER WITH HIGH TUMOR PD-L1

[0148] EXPRESSION

[0149] Anti-programmed cell death protein 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-Ll) antibodies as monotherapies or in combination with chemotherapy are the standard of care for first-line treatment of PD-L1 -positive locally advanced and metastatic non-small cell lung cancer (mNSCLC) in the absence of activating mutations (Hendriks LE et al. Ann Oncol. 2023;34:358-376). The addition of anti angiogenic agents to standard first-line treatment with a PD-L1 inhibitor and platinum -based chemotherapy has shown modest efficacy in patients with nonsquamous mNSCLC (Socinski MA et al. J Thorac Oncol. 2021;16:1909-1924.).

[0150] Ivonescimab, a bispecific antibody against PD-1 and VEGF-A showed promising clinical efficacy in a phase 3 trial (HARMONi-2) in China (HARMONI-A study investigators. JAMA. 2024;332:561-570 and Xiong A et al. Lancet. 2025;405(10481):839-849). In HARMONi-2, PFS improved significantly in patients with PD-L1 -positive (tumor proportion score [TPS] >1%) advanced NSCLC with ivonescimab compared with pembrolizumab (median PFS, 11.14 and 5.82 months, respectively; hazard ratio, 0.51; P < 0.0001). Results of the trial also showed an acceptable safety profile for ivonescimab, including in patients with squamous and nonsquamous NSCLC.

[0151] HARMONi-7 (NCT06767514) is a global, randomized, double-blind, phase 3 study comparing efficacy and safety of ivonescimab against pembrolizumab monotherapy in human patients with stage IV mNSCLC with high tumor PD-L1 expression and no known actionable genomic alterations who have not previously received systemic therapy for metastatic disease. Approximately 780 patients (subjects) are randomly assigned (1:1) to receive ivonescimab 20 mg / kg or pembrolizumab 200 mg every 3 weeks (Q3W) for up to 24 months. Antibody is administered by intravenous injection. Randomization is stratified according to histology (squamous vs nonsquamous), brain metastases at study entry (presence vs absence), and geographic region.Study inclusion criteria: >18 years of age at time of enrollment; metastatic (stage IV) NSCLC per the AJCC; ECOG PS score of 0 or 1; histologically or cytologically confirmed squamous or nonsquamous NSCLC; tumor with high PD-L1 expression based on a 22C3 (TPS >50%) or SP263 (TC >50%) IHC clinical assay, approved and cleared by local health authorities; >1 measurable noncerebral lesion per RECIST; expected life expectancy >3 months, and no prior systemic treatment for metastatic NSCLC.

[0152] Study exclusion criteria: histologic or cytopathologic evidence of NSCLC for which approved first-line therapies are indicated (for patients with nonsquamous histology, actionable genomic alteration testing results are required before randomization); known actionable genomic alterations for which approved first-line therapies are indicated (EGFR, ALK, ROS1, and BRAF V600E); any prior therapy for NSCLC in the metastatic setting, though local radiation therapy (plus / minus corticosteroids) for CNS or bone metastases is allowed; concurrent enrollment in another clinical study, other than a noninterventional clinical study or completion of a survival follow-up; symptomatic CNS metastases, CNS metastases with hemorrhagic features, CNS metastasis >1.5 cm, CNS radiation within 7 days before randomization, potential need for CNS radiation within the first cycle, or leptomeningeal disease (patients must have stopped corticosteroids or be on physiologic corticosteroid replacement therapy (prednisone < 10 mg daily or equivalent); other previous malignant neoplasm (including previously treated NSCLC) unless the patient has undergone curative therapy with no evidence of recurrence of the disease for 3 years before randomization, except the following after adequate treatment: basal cell or squamous cell carcinoma of skin, superficial bladder cancer, in situ cervical cancer, other in situ cancers, prostate cancer that does not need therapy, or other local tumors that are considered cured; active autoimmune or lung disease necessitating systemic therapy; preexisting peripheral neuropathy that is grade >2 by CTCAE; severe infection within 4 weeks before randomization; > 30 Gy of chest radiation therapy within 6 months prior to randomization; non-thoracic radiation therapy > 30 Gy within 4 weeks prior to randomization, or palliative radiation therapy of < 30 Gy within 7 days prior to randomization; major surgical procedures or serious trauma within 4 weeks before randomization; history of noninfectious pneumonia necessitating systemic corticosteroids or current interstitial lung disease; known history of human immunodeficiency virus (HIV) whose viral load is not controlled; imaging during the screening period shows that the patient has: (a) radiologically documented evidence of majorblood vessel invasion (central pulmonary artery, central pulmonary veins, aorta, brachiocephalic artery, common carotid artery, subclavian artery, superior vena cava) or tumor invading organs (heart, trachea, esophagus, central bronchi [not including segmental bronchi]) or if there is a risk of esophagotracheal or esophagopleural fistula in the opinion of the investigator, or (b) radiographic evidence of major blood vessel encasement with narrowing of the vessel or intratumor lung cavitation or necrosis that the investigator determines poses a significantly increased risk of bleeding; history of any grade arterial thromboembolic event, Grade 3 or above venous thromboembolic event as specified in the CTCAE, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to randomization; poorly controlled hypertension with repeated systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg after oral antihypertensive therapy; patients with active hepatitis B are required to have stable or declining levels of hepatitis B DNA by polymerase chain reaction (PCR) on appropriate anti-viral therapy with acceptable tolerability for one month prior to randomization; all patients with active hepatitis C (hepatitis C virus [HCV] antibody positive with HCV RNA levels above the lower limit of detection) are excluded; pre-existing peripheral neuropathy that is > Grade 2 by CTCAE.

[0153] Therapy is administered until: an intolerable toxicity occurs; disease progression occurs; or 24 months after the first dose. Both primary prophylaxis and secondary prophylaxis are allowed.

[0154] Primary study end points: overall survival (OS) and progression free survival (PFS) assessed by an independent radiology review committee (IRRC) per RECIST.

[0155] Secondary study endpoints: objective response rate (ORR), disease control rate (DCR), and duration of response (DoR), assessed by investigator based on RECIST; safety, assessed by incidence and severity of adverse events (AEs) and clinically significant abnormal laboratory test results for up to 90 days after the last dose of study (ivonescimab or pembrolizumab) treatment or initiation of other cancer therapy, whichever occurs first; and pharmacokinetics of ivonescimab and immunogenicity assessments, occurring throughout the study. OR, PFS, ORR, DCR, and DoR are assessed for up to approximately 36 months from first dosing. Pharmacokinetic characteristics (ivonescimab serum drug concentration profiles) are monitored. Immunogenicity (number and percentage of patients with detectable adenosine deaminase (ADA) at baseline and post treatment) is monitored. AEs and clinicallysignificant abnormal laboratory test results are assessed for up to approximately 36 months from first dosing.

[0156] Exploratory endpoints: potential biomarkers in tumor tissue and peripheral blood; intracranial PFS by IRRC, based on RECIST vl .1; HRQoL assessment using the EuroQol-5D-5L (EQ-5D-5L), European Organization for Cancer Research and Treatment Quality of Life - Core 30 Questionnaire (EORTC QLQ- C30), and European Organization for Cancer Research and Treatment Quality of Life - Lung Cancer 13 Questionnaire (EORTC QLQ-LC13).

[0157] The study includes sites in Europe, Japan, and North America.

[0158] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet, including U.S. Provisional Patent Application No. 63 / 777,591, filed March 25, 2025, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

[0159] These and other changes can be made to the embodiments in light of the abovedetailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS1. A method for treating a metastatic non-small cell lung cancer in a subject, the method comprising administering to the subject an effective amount of an antibody that binds:one or more of PD-1, PD-L1, and PD-L2, thereby blocking a PD-l / PD-1 ligand interaction; and one or more of VEGFR1, VEGFR2, VEGFR3, VEGF-A, VEGF- B, VEGF-C, VEGF-D, and PIGF, thereby blocking a VEGFR / VEGFR ligand interaction, wherein, optionally, the antibody binds: PD-1 and a VEGF, preferably VEGF-A; PD-L1 and a VEGFR, preferably VEGFR-2 or VEGFR-1; PD-L1 and a VEGF, preferably VEGF-A; PD-1 and a VEGFR, preferably VEGFR-2 or VEGFR-1; PD-1, CTLA4, and a VEGF; PD-1, TGF0, and a VEGF; or PD-L1, a VEGF, and TGF[3.

2. The method of claim 1, wherein the antibody binds PD-1 and VEGF-A.

3. The method of claim 1 or 2, wherein the antibody comprises a VEGF-A-binding domain comprising the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs.3-5 and 7-9, respectively, and a PD-1- binding domain comprising the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs.:12-14 and 15-17, respectively.

4. The method of any one of claims 1-3, wherein the antibody comprises a VEGF-A binding domain comprising the VH amino acid sequence of SEQ ID NO:6 and the VL amino acid sequence of SEQ ID NO:9, and / or wherein the antibody comprises a PD-1 binding domain comprising the VH amino acid sequence EVQLVESGGGLVQPGGSLRLSC AASGFAF S S YDMSWVRQ APGKGLDWVA TISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANR YGEAWFAYWGQGTLVTVSS (SEQ ID NO: 16) and the VL amino acid sequence DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRA NRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGT KLELKR (SEQ ID NO: 19).

5. The method of any one of claims 1-4, wherein the antibody comprises a tetravalent structure.

6. The method of any one of claims 1-5, wherein the antibody is in a IgG-scFv format, wherein, optionally, the IgG portion comprises a binding domain that binds one or more of VEGFR1, VEGFR2, VEGFR3, VEGF-A, VEGF-B, VEGF- C, VEGF-D, and PIGF, and wherein the scFv portion comprises two scFvs that each bind one or more of one of PD-1, PD-L1, and PD-L2, wherein, further optionally, the IgG portion comprises a binding domain that binds to VEGF-A and the scFv portion comprises two scFvs that each bind PD-1.

7. The method of any one of claims 1-6, wherein the antibody comprises a modified IgGl Fc domain comprising one or more mutations that reduce effector function of the antibody, where, optionally, the one or more mutations comprise the mutations L234A and L235A.

8. A method for treating a metastatic non-small cell lung cancer in a subject, the method comprising administering to the subject an effective amount of an antibody, wherein the antibody comprises ivonescimab.

9. The method of any one of claims 1-8, comprising administering to the subject a single dose or a plurality of doses of the antibody, or of a pharmaceutical composition comprising the antibody, wherein a dose is 20 mg / kg (of the subject’s body weight) of the antibody or pharmaceutical composition, optionally by intravenous administration and / or once every three weeks.

10. The method of claim 9, comprising administering to the subject a single dose or a plurality of doses of the antibody, or of a pharmaceutical composition comprising the antibody, wherein a dose is 20 mg / kg (of the subject’s body weight) of the antibody or pharmaceutical composition, by intravenous administration, once every three weeks.

11. The method of any one of claims 1-10, wherein the non-small cell lung cancer has been determined to comprise one or more tumors having PD-L1 expression on atleast 50% of tumor cells as determined by immunohistochemical analysis of tumor tissue.

12. The method of any one of claims 1-11, wherein the non-small cell lung cancer has been determined to comprise one or more tumors having high PD-L1 expression as determined by TPS >50%, based on a PD-L1 22C3 immunohistochemical assay.

13. The method of any one of claims 1-12, wherein the non-small cell lung cancer has been determined to comprise one or more tumors having a high PD-L1 expression of TC >50%, based on aPD-Ll SP263 immunohistochemical assay.

14. The method of any one of claims 12-13, wherein the PD-L1 expression is determined from existing immunohistochemical assay results.

15. The method of any one of claims 12-14, wherein the PD-L1 expression is determined from archival or fresh tumor tissue.

16. The method of any one of claims 1-15, wherein the subject has not previously received systemic therapy for metastatic non small cell lung cancer.

17. The method of any one of claims 1-16, wherein the subject has an ECOG PS score of 0 or 1.

18. The method of any one of claims 1-17, wherein the subject has a stage IV metastatic non-small cell lung cancer according to American Joint Committee on Cancer (AJCC) guidelines.

19. The method of any one of claims 1-18, wherein the subject has squamous or nonsquamous non-small cell lung cancer.

20. The method of any one of claims 1-19, wherein the subject:a. is 18 years of age or older;b. has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1;c. has one or more measurable noncerebral lesion per RECIST vl.l; d. has histologically or cytologically confirmed squamous or non-squamous non-small cell lung cancer;e. has not received prior systemic treatment for metastatic non-small cell lung cancer;f. has a creatinine clearance (CrCl) > 30 mL / min using the Cockcroft-Gault formula;g. has an estimated glomerular filtration rate (eGFR) value > 30 mL / min using the Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) equation;h. has urine protein <2+ or 24-hour urine protein quantification <1.0 gram; i. has no known actionable genetic alterations (e.g., no actionable genetic alterations in EGFR, ALK, ROS1, or BRAFV600EL), optionally for which one or more first-line approved therapy is indicated; and / orj. has an expected life expectancy of >3 months.

21. The method of any one of claims 1-20, wherein the subject, prior to receiving the antibody or a pharmaceutical composition comprising the antibody:a. does not have symptomatic CNS metastases, CNS metastasis > 1.5 cm, and / or CNS radiation within 7 days;b. is not a candidate for CNS radiation;c. does not have leptomeningeal disease;d. does not have an autoimmune or lung disease requiring systemic therapy; e. does not have a pre-existing peripheral neuropathy that is > Grade 2 by CTCAE version 5;f. does not have a severe infection;g. has not had a major surgical procedure or serious trauma within 4 weeks; h. has one or more known actionable genetic alteration (e.g., actionable genetic alteration in EGFR, ALK, ROS1, or BRAFV600EL), optionally for which one or more first-line approved therapy is indicated;i. does not have a history of noninfectious pneumonia requiring systemic corticosteroids; and / orj . does not have lung interstitial disease.

22. The method of any one of claims 1-21, wherein the method does not comprise administering an additional non-small cell lung cancer therapeutic agent to the subject.

23. The method of any one of claims 1-22, wherein, subsequent to administering the antibody, the subject experiences: a partial response; a complete response; progression-free survival (PFS), or overall survival (OS) for 4 months, 5 months, 6 months, 12 months, 15 months, 18 months, a 24 months, 30 months, or 36 months or more.