Agonistic separation antibodies

Abstract

The present application relates to a pair of antigen binding molecules, each molecule comprising a target binding domain, a cytokine receptor binding domain and an Fc domain wherein the target binding domain concurrently binds to a target antigen and the cytokine receptor binding domain binds to a subunit of a cytokine receptor complex. Biparatome assembly of the cytokine receptor binding domain in the presence of the target antigen allows for selective activation of cytokine receptors and efficient mimicking of cytokine activity in a targeted manner.

Description

TECHNICAL FIELD

[0001] The present application relates to pairs of antigen binding molecules, each molecule comprising a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the target binding domains bind to a target antigen simultaneously and the cytokine receptor binding domains bind to a subunit of a cytokine receptor complex. The biparatopic assembly of the cytokine receptor binding domains in the presence of the target antigen allows for selective activation of the cytokine receptor and effective mimicry of cytokine activity in a targeted manner. BACKGROUND

[0002] In recent years, immunotherapy treatments for cancer have grown dramatically, and cancer immunotherapy is becoming a major strategy against the disease. For many cancer types, immune checkpoint modulators, including anti-PD-1, have become the standard of care. However, despite the many advances in the field of cancer immunotherapy treatments in recent years, a significant proportion of patients still do not respond to existing immunotherapies due to intrinsic or adaptive resistance mechanisms. Patients with non-inflammatory immune disorders under cancer immunotherapy are more likely to fail to respond to immunotherapy. Immune cell infiltration in tumors has been shown to correlate with the ability of patients to respond to immunotherapy treatment. Developing new therapies aimed at increasing immune cell infiltration and enhancing immunogenicity is critical for patients.

[0003] In parallel with the above developments, cytokines have gained widespread attention as potential cancer treatments. IFNy (interferon gamma or IFN-gamma) is a cytokine that is primarily produced by activated lymphocytes (such as CD4 + and CD8 + T cells) and natural killer cells (NK cells) in response to immunological or inflammatory stimuli. IFNy is a homodimer, and its receptors (IFNyR1 and IFNyR2) are expressed in hematopoietic and non-hematopoietic cells. At the cell surface, IFNyR1 is stably expressed, while IFNyR2 is differentially expressed and regulates IFNy. When IFNy binds to its receptor, Janus kinases JAK1 and JAK2 are recruited and activated, which phosphorylate and activate STAT1. Phosphorylated STAT1 translocates to the nucleus, binds to promoters, and regulates gene transcription under the control of IFNy.

[0004] In contrast to other cancer therapies existing or being developed in the market, IFNy can act on both tumor cells and immune cells, including T cells and dendritic cells. The effects of IFNy on different cell types have several benefits, which include 1) enhancing the expression of surface MHC-I molecules on both tumor cells and antigen-presenting cells, 2) recruiting immune cells to the tumor site by inducing the production of CXCL9, CXCL10, and CXCL11, and 3) increasing the ability of tumor antigen cross-presentation, subsequently enhancing the anti-tumor immune response. In addition to these effects, IFNy promotes the formation of Th1 environment, monocyte differentiation, macrophage polarization, and angiogenesis. Since IFNy receptors are expressed on multiple cell types, sink effects can reduce its activity.

[0005] IFNy can also show undesirable side effects. In addition, problems of short administration, bioavailability, and half-life can occur. Therefore, there is a need for new molecules that can selectively activate the IFNy pathway at the tumor site.

[0006] The targeting of the interleukin 2 (IL-2) pathway as a cancer immunotherapy strategy has a long and complex history, both witnessing the brilliant achievements of this clinical approach and revealing its inherent complexity. IL-2 is a cytokine that activates lymphocytes and natural killer (NK) cells. Clinical efficacy is often overshadowed by reports of IL-2 related toxicities and CD25 mediated complications associated with peripheral T cell activity.

[0007] Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but there are several limitations to native cytokines as therapeutic agents. Low stability and difficulties in production processes are just some of them. For some time, it has been known that antibodies can induce signaling on cells and thus replace the natural ligand.

[0008] In recent literature, increasing evidence suggests that using both antibody- and non-antibody-based protein scaffolds to bring heterodimeric cytokine receptors together is a viable strategy to mimic natural cytokine activity. For example, Moraga and colleagues provided an early example of using diabodies as surrogate ligands for the erythropoietin receptor (EpoR) (Moraga et al. Cell 160, 1196-1208 (2015)). Researchers at Teneobio used the knobs-into-holes technology to combine two pure heavy chain antibodies (VHHs fused to Fc domains) directed against different epitopes on the interleukin-2 receptor (IL-2Rβ and IL-2Rγ) into a bispecific null IgG4 Fc (CH1 -deficient). While monospecific anti-IL-2Rβ or anti-IL-2Rγ, alone or mixed, did not activate human CD8 +STAT5 phosphorylation on T cells, but bispecific anti-IL-2Rβγ antibodies showed different levels of agonist activity (Harris, K. E. et al. Sci Rep 11(1): 10592 (2021)). Scientists at Synthekine adopted a similar approach described by Teneobio that described functional induction of signaling via two interleukin receptors (IL-2Rβ and IL-2Rγ) by single domain antibodies (sdAbs; WO 2022 / 032040 Al) and reviewed by Saxton and colleagues (Saxton, R. A. et al. Nat Rev Drug Discov. 22, 21-37 (2022)). Researchers at Stanford University further expanded this approach where the authors proposed a strategy to discover cytokine surrogate agonists by using modular ligands such as human VHHs or scFvs against interleukin-2 / 15, type I interferons, and interleukin-10 receptors. Interestingly, they also identified functional, non-native assemblies such as the IL-2Rβ / IL-10Rβ heterodimer (Yen, M. et al. Cell 185(8): 1414-1430 e1419 (2022)). The same authors also discussed a structure-based approach for the decoupling of pro- and anti-inflammatory functions of interleukin-10 (Saxton, R. A. et al. Science 371(6535) (2021)). Two academic research groups from the Czech Republic and Israel jointly reported the discovery of non-antibody-based scaffolds that mimic the cytokine IFNλ. Combinatorial libraries derived from several established small protein scaffolds were used to identify variants capable of binding to IFNλR1 or IL-10Rβ and inducing functional signaling (Kolarova, L. et al. FEBS J 289(9): 2672-2684 (2022)). Researchers at Medikine addressed the problem of downsizing agonistic modules. They obtained molecules selected from a peptide library through a screen aimed at identifying molecules that bind to both the Rα and γc subunits of the human IL-7 receptor. Those peptides with a molecular weight of less than 5 kDa fused to an IgG1-Fc domain showed similar biological properties to IL-7 in vitro and when administered to non-human primates (Dower, W. et al. Journal for ImmunoTherapy of Cancer 8 (Suppl 3): A341-A342 (2020)).

[0009] Due to the pleiotropic effects of cytokines, new approaches are needed to selectively activate cytokine receptors and effectively mimic cytokine activity. SUMMARY

[0010] The present invention relates to new antigen binding molecules comprising cytokine receptor binding domains for use as cytokine mimics selectively activating receptor pathways under the required conditions of bi-paratopic assembly on a target antigen.

[0011] The present invention relates to a pair of antigen binding molecules that specifically bind to a target antigen, the pair of antigen binding molecules comprising: a) a first antigen binding molecule comprising i) a first target binding domain, ii) a first cytokine receptor binding domain, and iii) an Fc domain; and b) a second antigen binding molecule comprising i) a second target binding domain, ii) a second cytokine receptor binding domain, and iii) an Fc domain; wherein the first target binding domain is capable of binding to a first epitope on the target antigen and the second target binding domain is capable of binding to a second epitope on the target antigen, wherein the first target binding domain and the second target binding domain do not compete for binding on the target antigen; and wherein the first cytokine receptor binding domain is capable of binding to a first cytokine receptor subunit and the second cytokine receptor binding domain is capable of binding to a second cytokine receptor subunit.

[0012] In one aspect, the first target binding domain and the second target binding domain are antibody fragments, such as Fv, Fab, scFv, scFab molecules or single domain antibodies. In one aspect, the first target binding domain and the second target binding domain are Fab molecules. In one aspect, the first target binding domain comprises a heavy chain variable domain (VH1), a light chain variable domain (VL1), a heavy chain constant domain (CH11), and a light chain constant domain (CL1), and wherein the second target binding domain comprises a heavy chain variable domain (VH2), a light chain variable domain (VL2), a heavy chain constant domain (CH12), and a light chain constant domain (CL2). In one aspect, the first target binding domain and / or the second target binding domain are cross-Fab molecules.

[0013] In one aspect, the first and second target binding domains specifically bind to a tumor- associated antigen or a T cell antigen. In one aspect, the first and second target binding domains specifically bind to FAP, PD-1, Her2, Her3, LAG-3, or EGFR. In one aspect, a) the first target binding domain comprises a VH1 of SEQ ID NO: 20 and a VL1 of SEQ ID NO: 21, and the second target binding domain comprises a VH2 of SEQ ID NO: 22 and a VL2 of SEQ ID NO: 23, or b) the first target binding domain comprises a VH1 of SEQ ID NO: 22 and a VL1 of SEQ ID NO: 23, and the second target binding domain comprises a VH2 of SEQ ID NO: 20 and a VL2 of SEQ ID NO: 21, or c) the first target binding domain comprises a VH1 of SEQ ID NO: 76 and a VL1 of SEQ ID NO: 77, and the second target binding domain comprises a VH2 of SEQ ID NO: 78 and a VL2 of SEQ ID NO: 79, or d) the first target binding domain comprises a VH1 of SEQ ID NO: 78 and a VL1 of SEQ ID NO: 79, and the second target binding domain comprises a VH2 of SEQ ID NO: 76 and a VL2 of SEQ ID NO: 77; or e) the first target binding domain comprises a VH1 of SEQ ID NO: 93 and a VL1 of SEQ ID NO: 94, and the second target binding domain comprises a VH2 of SEQ ID NO: 78 and a VL2 of SEQ ID NO: 79; or f) the first target binding domain comprises a VH1 of SEQ ID NO: 78 and a VL1 of SEQ ID NO: 79, and the second target binding domain comprises a VH2 of SEQ ID NO: 93 and a VL2 of SEQ ID NO: 94, or g) the first target binding domain comprises a VH1 of SEQ ID NO: 130 and a VL1 of SEQ ID NO: 131, and the second target binding domain comprises a VH2 of SEQ ID NO: 132 and a VL2 of SEQ ID NO: 133.or h) the first target binding domain comprises a VH1 of SEQ ID NO: 132 and a VL1 of SEQ ID NO: 133, and the second target binding domain comprises a VH2 of SEQ ID NO: 130 and a VL2 of SEQ ID NO: 131; or i) the first target binding domain comprises a VH1 of SEQ ID NO: 140 and a VL1 of SEQ ID NO: 141, and the second target binding domain comprises a VH2 of SEQ ID NO: 142 and a VL2 of SEQ ID NO: 143; or j) the first target binding domain comprises a VH1 of SEQ ID NO: 142 and a VL1 of SEQ ID NO: 143, and the second target binding domain comprises a VH2 of SEQ ID NO: 140 and a VL2 of SEQ ID NO: 141; or k) the first target binding domain comprises a VH1 of SEQ ID NO: 114 and a VL1 of SEQ ID NO: 115, and the second target binding domain comprises a VH2 of SEQ ID NO: 116 and a VL2 of SEQ ID NO: 117; or l) the first target binding domain comprises a VH1 of SEQ ID NO: 116 and a VL1 of SEQ ID NO: 117, and the second target binding domain comprises a VH2 of SEQ ID NO: 114 and a VL2 of SEQ ID NO: 115; or m) the first target binding domain comprises a VH1 of SEQ ID NO: 150 and a VL1 of SEQ ID NO: 151, and the second target binding domain comprises a VH2 of SEQ ID NO: 152 and a VL2 of SEQ ID NO: 153; or n) the first target binding domain comprises a VH1 of SEQ ID NO: 152 and a VL1 of SEQ ID NO: 153, and the second target binding domain comprises a VH2 of SEQ ID NO: 150 and a VL2 of SEQ ID NO: 151.

[0014] In one aspect, the first and second cytokine receptor subunits are both subunits of an IFNy receptor complex or an IL-2 receptor complex or an IL-7 receptor complex. In one aspect, a) the first cytokine receptor binding domain is capable of binding IFNyRl and the second cytokine receptor binding domain is capable of binding IFNyR2, or b) the first cytokine receptor binding domain is capable of binding IFNyR2 and the second cytokine receptor binding domain is capable of binding IFNyRl ; or c) the first cytokine receptor binding domain is capable of binding IL-2Rβ and the second cytokine receptor binding domain is capable of binding IL-2Rγ, or d) the first cytokine receptor binding domain is capable of binding IL-2Rγ and the second cytokine receptor binding domain is capable of binding IL-2Rβ; or e) the first cytokine receptor binding domain is capable of binding IL-2Rγ and the second cytokine receptor binding domain is capable of binding IL-7Rα; or f) the first cytokine receptor binding domain is capable of binding IL-7Rα and the second cytokine receptor binding domain is capable of binding IL-2Rγ.

[0015] In one aspect, the first and second cytokine receptor binding domains are antibody fragments, such as Fv, Fab, scFv, scFab, or single domain antibodies. In one aspect, the first and second cytokine receptor binding domains are VHH domains. In one aspect, a) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 5, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, or b) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 5; or c) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58 SEQ ID NO: 60, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65; or d) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58 SEQ ID NO: 60.or e) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65; or f) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192.

[0016] In one aspect, a) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 3 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 7, or b) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 7 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 3; or c) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 60 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, or d) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 60; or e) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 186 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, or f) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 186.

[0017] In one aspect, the Fc domain of the first and second antigen binding molecules comprises a first Fc domain subunit and a second Fc domain subunit. In one aspect, the Fc domain of the first and second antigen binding molecules is an IgG Fc domain, in particular an IgGl Fc domain. In one aspect, the Fc domain of the first and second antigen binding molecules is a human Fc domain. In one aspect, the Fc domain of the first and second antigen binding molecules comprises a modification that promotes association of the first subunit with the second subunit of the Fc domain. In one aspect, the Fc domain of the first and second antigen binding molecules comprises one or more amino acid substitution that reduces binding to an Fc receptor and / or effector function.

[0018] In one aspect, the cytokine receptor binding domains are fused to their respective fusion point via a peptide linker. In one aspect, the peptide linker comprises an amino acid sequence selected from SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 279, SEQ ID NO: 280, or SEQ ID NO: 281.

[0019] In one aspect, the first cytokine receptor binding domain is fused at its C-terminus to the N-terminus of VH1 or VL1 of the first target binding domain, and the second cytokine receptor binding domain is fused at its C-terminus to the N-terminus of VH2 or VL2 of the second target binding domain.In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a VH1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a VH2, a CH12, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL2, and a CL2; or b) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a VL1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH2, a CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a VL2, and a CL2; or c) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a VH1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH2, a CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a VL2, and a CL2; wherein the VH1, the VL1, the CH11, and the CL1 form a first target binding domain, and the VH2, the VL2, the CH12, and the CL2 form a second target binding domain.

[0020] In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a VH1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a VH2, a CH12, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL2, and a CL2; or b) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a VL1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH2, a CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a VL2, and a CL2; or c) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a VH1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH2, a CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a VL2, and a CL2; or d) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a VL1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VH1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH2, a CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a VL2, and a CL2.and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, from N-terminus to C-terminus, a second cytokine receptor binding domain, a VL2, a CL2, and a second Fc domain subunit; and a third polypeptide comprising, from N-terminus to C-terminus, a VH2, a CH12, and a first Fc domain subunit; or e) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, from N-terminus to C-terminus, a VL1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, from N-terminus to C-terminus, a first cytokine receptor binding domain, a VH1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, from N-terminus to C-terminus, a VH2, a CH12, and a second Fc domain subunit; a third polypeptide comprising, from N-terminus to C-terminus, a second cytokine receptor binding domain, a VL2, and a CL2; or f) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, from N-terminus to C-terminus, a first cytokine receptor binding domain, a VL1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, from N-terminus to C-terminus, a VH1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, from N-terminus to C-terminus, a VH2, a CH12, and a second Fc domain subunit; and a third polypeptide comprising, from N-terminus to C-terminus, a second cytokine receptor binding domain, a VL2, and a CL2; or g) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, from N-terminus to C-terminus, a VL1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, from N-terminus to C-terminus, a first cytokine receptor binding domain, a VH1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, from N-terminus to C-terminus, a second cytokine receptor binding domain, a VH2, a CH12, and a second Fc domain subunit; and a third polypeptide comprising, from N-terminus to C-terminus, a VL2, and a CL2.wherein VH1, VL1, CH11, and CL1 form a first target binding domain, and VH2, VL2, CH12, and CL2 form a second target binding domain.

[0021] In one aspect, the first and second target binding domains specifically bind to FAP and the first and second cytokine receptor subunits are subunits of an IFNy receptor complex. Thus, in one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 27; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 30; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 38; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 37; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 31; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 33; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 35; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 33.and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 33; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 30; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 31 ; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 38; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 36; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 37; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 35.

[0022] In one aspect, the first and second target binding domains specifically bind to EGFR, and the first and second cytokine receptor subunits are subunits of an IFNy receptor complex. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 260; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 259; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 256; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 122; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 255; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 261; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 258; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 257; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 122; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 255.the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 255; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 256; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 259; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 261; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 254; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 257; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 259; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127.a second polypeptide comprising the amino acid sequence of SEQ ID NO: 258; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127.

[0023] In one aspect, the first and second target binding domains specifically bind to PD-1, and the first and second cytokine receptor subunits are subunits of an IL-2 receptor complex. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 86; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 83; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 87; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 92; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 91; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 95; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 101; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 99; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 87.and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 103; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 100; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 104; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 99; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 101 ; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 95; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 102.or i) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 100; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 103; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or j) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 97; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 104.

[0024] In one aspect, the first and second target binding domains specifically bind to LAG-3 and the first and second cytokine receptor subunits are subunits of an IL-2 receptor complex. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 162; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159.the second polypeptide comprises the amino acid sequence of SEQ ID NO: 158; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 157; or e) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161 ; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 162; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159.a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 157.

[0025] The first and second target binding domains specifically bind to EGFR, and the first and second cytokine receptor subunits are subunits of an IL-2 receptor complex. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 162; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159.the second polypeptide comprises the amino acid sequence of SEQ ID NO: 161 ; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 162; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159.a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 157.

[0026] In one aspect, the first and second target binding domains specifically bind to FAP and the first and second cytokine receptor subunits are subunits of an IL-2 receptor complex. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 110; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 113; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 105; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 109; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 111; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 107; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 109.the second polypeptide comprises the amino acid sequence of SEQ ID NO: 34; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or e) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 110; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 109; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 105; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 113; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 111; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 108; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 107; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 109; or i) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 105; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 113; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or j) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 111; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 108; or k) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 107; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 109.and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0027] In one aspect, the first and second target binding domains specifically bind to Her2 and the first and second cytokine receptor subunits are subunits of an IL-2 receptor complex. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 136; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 134; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 138; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 137; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 135; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 134; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 138; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 139.

[0028] In one aspect, the first and second target binding domains specifically bind to Her3 and the first and second cytokine receptor subunits are subunits of an IL-2 receptor complex. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 146; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 144; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 148; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 147; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 145; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 144; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 148; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 149.

[0029] In one aspect, the first and second target binding domains specifically bind to PD-1 and the first and second cytokine receptor subunits are subunits of an IL-7 receptor complex. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 194; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 193; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 195; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 196; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 197; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.the second polypeptide comprises the amino acid sequence of SEQ ID NO: 90; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 89; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 198; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or e) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 199; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 200; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 201 ; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO:28; a second polypeptide comprising the amino acid sequence of SEQ ID NO:90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:89; or j) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 204; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO:28; a second polypeptide comprising the amino acid sequence of SEQ ID NO:90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:89; or k) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 205; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO:28; a second polypeptide comprising the amino acid sequence of SEQ ID NO:90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:89.

[0030] In one aspect, the first target binding domain is fused at its C-terminus to the N- terminus of a first Fc domain subunit and the first cytokine receptor binding domain is fused at its C-terminus to the N-terminus of a second Fc domain subunit and the second target binding domain is fused at its C-terminus to the N-terminus of a first Fc domain subunit and the second cytokine receptor binding domain is fused at its C-terminus to the N-terminus of a second Fc domain subunit. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide which comprises, from N-terminus to C-terminus in order, a VH1, a CH11, and a first Fc domain subunit; a second polypeptide which comprises, from N-terminus to C-terminus in order, a VL1, and a CL1; and a third polypeptide which comprises, from N-terminus to C-terminus in order, a first cytokine receptor binding domain and a second Fc domain subunit; and the second antigen binding molecule comprises: a first polypeptide which comprises, from N-terminus to C-terminus in order, a VH2, a CH12, and a first Fc domain subunit; a second polypeptide which comprises, from N-terminus to C-terminus in order, a VL2, and a CL2; and a third polypeptide which comprises, from N-terminus to C-terminus in order, a second cytokine receptor binding domain and a second Fc domain subunit; or b) the first antigen binding molecule comprises: a first polypeptide which comprises, from N-terminus to C-terminus in order, a VL1, a CH11, and a first Fc domain subunit; a second polypeptide which comprises, from N-terminus to C-terminus in order, a VH1, and a CL1; and a third polypeptide which comprises, from N-terminus to C-terminus in order, a first cytokine receptor binding domain and a second Fc domain subunit; and the second antigen binding molecule comprises: a first polypeptide which comprises, from N-terminus to C-terminus in order, a VH2, a CH12, and a first Fc domain subunit; a second polypeptide which comprises, from N-terminus to C-terminus in order, a VL2, and a CL2; and a third polypeptide which comprises, from N-terminus to C-terminus in order, a second cytokine receptor binding domain and a second Fc domain subunit; wherein the VH1, the VL1, the CH11, and the CL1 form the first target binding domain and the VH2, the VL2, the CH12, and the CL2 form the second target binding domain. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide which comprises the amino acid sequence of SEQ ID NO: 32; a second polypeptide which comprises the amino acid sequence of SEQ ID NO: 25; and a third polypeptide which comprises the amino acid sequence of SEQ ID NO: 39; and b) the second antigen binding molecule comprises: a first polypeptide which comprises the amino acid sequence of SEQ ID NO: 32; a second polypeptide which comprises the amino acid sequence of SEQ ID NO: 25; and a third polypeptide which comprises the amino acid sequence of SEQ ID NO: 39.and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 34; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 40; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 34; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 39; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 32; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 40; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 237; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 238; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 235; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 236; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or e) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 239; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 240; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 237; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 236; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 235; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 240; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 239; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0031] In one aspect, wherein the first target binding domain is fused at the C-terminus of its CH11 to the N-terminus of one of the Fc domain subunits and the first cytokine receptor binding domain is fused at the N-terminus thereof to the C-terminus of the same Fc domain subunit and the second target binding domain is fused at the C-terminus of its CH12 to the N-terminus of one of the Fc domain subunits and the second cytokine receptor binding domain is fused at the N-terminus thereof to the C-terminus of the same Fc domain subunit. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, a VH1, a CH11, a second Fc domain subunit, and a first cytokine receptor binding domain; and a third polypeptide comprising, in N-terminal to C-terminal order, a VL1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, a VH2, a CH12, a second Fc domain subunit, and a second cytokine receptor binding domain; and a third polypeptide comprising, in N-terminal to C-terminal order, a VL2, and a CL2; or b) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, a VL1, a CH11, a second Fc domain subunit, and a first cytokine receptor binding domain; and a third polypeptide comprising, in N-terminal to C-terminal order, a VH1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, a VH2, a CH12, a second Fc domain subunit, and a second cytokine receptor binding domain; and a third polypeptide comprising, in N-terminal to C-terminal order, a VL2, and a CL2; or c) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, a VL1, a CH11, a second Fc domain subunit, and a first cytokine receptor binding domain; and a third polypeptide comprising, in N-terminal to C-terminal order, a VH1, and a CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, a VH2, a CH12, a second Fc domain subunit, and a second cytokine receptor binding domain; and a third polypeptide comprising, in N-terminal to C-terminal order, a VL2, and a CL2.and a third polypeptide comprising, in N-terminal to C-terminal order, VL2 and CL2; wherein VH1, VL1, CH11, and CL1 form a first target binding domain and VH2, VL2, CH12, and CL2 form a second target binding domain. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 42; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 41; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 45; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 43; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 46; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 41; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 47; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 43; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 246; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 249; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 242; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 249; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.the second polypeptide comprises the amino acid sequence of SEQ ID NO: 250; and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241 ; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 253; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241 ; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 248; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241 ; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 247; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241 ; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 244; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241 ; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 243; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241 ; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 252; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241 ; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 251 ; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.and the third polypeptide comprises the amino acid sequence of SEQ ID NO: 29; or i) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 42; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 42; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 245; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0032] In one aspect, the first and second cytokine receptor binding domains of the pair of antigen binding molecules are Fab molecules. In one aspect, a) the first cytokine receptor binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 282 and a VL domain comprising the amino acid sequence of SEQ ID NO: 283, or the first cytokine receptor binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 284 and a VL domain comprising the amino acid sequence of SEQ ID NO: 285; and the second cytokine receptor domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 286 and a VL domain comprising the amino acid sequence of SEQ ID NO: 287, or the second cytokine receptor domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 288 and a VL domain comprising the amino acid sequence of SEQ ID NO: 289; or b) the first cytokine receptor binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 286 and a VL domain comprising the amino acid sequence of SEQ ID NO: 287, or the first cytokine receptor binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 288 and a VL domain comprising the amino acid sequence of SEQ ID NO: 289; and the second cytokine receptor domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 282 and a VL domain comprising the amino acid sequence of SEQ ID NO: 283, or the second cytokine receptor domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 284 and a VL domain comprising the amino acid sequence of SEQ ID NO: 285.16.

[0033] In one aspect, the first and second cytokine receptor binding domains of the pair of antigen binding molecules are scFv molecules. In one aspect, a) the first cytokine receptor binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 290 and a VL domain comprising the amino acid sequence of SEQ ID NO: 291 ; and the second cytokine receptor domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 292 and a VL domain comprising the amino acid sequence of SEQ ID NO: 293; or b) the first cytokine receptor binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 292 and a VL domain comprising the amino acid sequence of SEQ ID NO: 293; and the second cytokine receptor domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 290 and a VL domain comprising the amino acid sequence of SEQ ID NO: 291.

[0034] In one aspect, the Fc domain of the first and second antigen binding molecules comprising a Fab or scFv molecule as a cytokine receptor binding domain comprises a first Fc domain subunit and a second Fc domain subunit. In one aspect, the Fc domain of the first and second antigen binding molecules is an IgG Fc domain, particularly an IgGl Fc domain. In one aspect, the Fc domain of the first and second antigen binding molecules is a human Fc domain. In one aspect, the Fc domain of the first and second antigen binding molecules comprises a modification that promotes association of the first subunit with the second subunit of the Fc domain. In one aspect, the Fc domain of the first and second antigen binding molecules comprises one or more amino acid substitutions that reduce binding to an Fc receptor and / or effector function. In one aspect, the cytokine receptor binding domain is fused to their respective fusion point via a peptide linker. In one aspect, the peptide linker comprises the amino acid sequence of SEQ ID NO: 280 or SEQ ID NO: 281. In one aspect, a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 267; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 265; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 266; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 272; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 271; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 267; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 265; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 266; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 274; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 271.and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 268; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 271; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 269; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 265; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 268; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 274; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 273. In one aspect, the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 276; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 275; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 277; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 278. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1. Schematic representation of antigens used for llama immunization, phage display and screening for the isolation of human IFNyRl, IFNyR2, IL-2Rß and IL-2Ry specific single domain antibodies. For llama immunization, heterodimers were generated from the extracellular domain (ECD) of human IFNyRl fused to a biotinylated Fc paddle and the ECD of human IFNyR2 fused to a Fc hole (A) and from the ECD of human IL-2Rß fused to a biotinylated Fc paddle and the ECD of human IL-2Ry fused to a Fc hole (D). For phage display, monovalent human IFNyRl fused to a biotinylated Fc (B), monovalent human IFNyR2 fused to a biotinylated Fc (C), monovalent human IL-2Rß fused to a biotinylated Fc (E), monovalent human IL-2Ry fused to a biotinylated Fc (F) and soluble Fc (G) were generated.

[0036] Figure 2. Workflow for the enrichment of single domain antibodies with binding specificity for human cytokine receptor subunits by phage display.

[0037] Figure 3. Specific screening of single domain antibodies by ELISA. A set of random soluble VHH domains selected for human IFNyRl specificity after three rounds of phage display were tested for binding to immobilized human IFNyRl-Fc and immobilized human Fc (A). VHH domains with human IFNyR2 specificity after three rounds of phage display were also tested for antigen specificity by ELISA (B). VHH domains selected for human IL-2Rß specificity after three rounds of phage display were tested for binding to immobilized human IL-2Rß-Fc and immobilized human Fc (C). VHH domains with human IL-2Ry specificity after three rounds of phage display were also tested for antigen specificity by ELISA (D). The absorbance at 450 nm indicative of the binding reaction to each target is represented as a stacked bar graph.

[0038] Figure 4. Format conversion of single domain antibody fragments. Third round VHH library variants with IFNyRl or IL-2Rß specificity were fused to Fc paddles and cloned into mammalian cell expression vectors using the Gibson cloning method (A). Third round VHH library variants with IFNyR2 or IL-2Ry specificity were fused to Fc holes using the same method (B).

[0039] Figure 5. Bispecific heavy chain antibodies comprising IFNyRl -IFNyR2 or IL-2R -IL-2Ry VHH domain pairs. VHH domains with specificity for IFNyRl or IL-2R were fused to the Fc knob and VHH domains targeting IFNyR2 or IL-2Ry were fused to the Fc hole. VHH moieties were fused to the Fc chains using a flexible 5 (G4S) linker. Bispecific heavy chain antibodies were generated via knob-in-hole assembly of the Fc chains. The effector function of the Fc was silenced via incorporation of the P329G LALA mutation in the CH2 domain.

[0040] Figure 6. Functional screening of bispecific heavy chain antibodies comprising IFNyRl -IFNyR2 or IL-2R -IL-2Ry VHH domain pairs. HEK-Blue IFNy cells were incubated with IFNy agonistic bispecific heavy chain antibodies comprising IFNyRl and IFNyR2 VHH domain pairs generated using the 5x5 bispecific matrix (A). HEK-Blue IL-2 reporter cells were incubated with IL-2 agonistic bispecific heavy chain antibodies comprising IL-2R and IL-2Ry VHH pairs generated using the 5x5 bispecific matrix (B). IFNyR activity and IL-2R activity were quantified by absorbance at 650 nm and the fold of response per background is shown for each treatment.

[0041] Figure 7. Characterization of dose-dependent responses of IFNy agonistic heavy chain antibodies. Previously identified IFNy agonists (Figure 6A, Table 1) were screened for dose-dependent IFNyR activity (characterized by absorbance at 650 nm) in HEK-Blue IFNy cells. The response of different IFNy agonistic heavy chain antibodies was grouped according to the anti-IFNyRl VHH clone, i.e. in each figure the anti-IFNyR2 VHH clone was variable while the anti-IFNyRl VHH clone remained constant: IFNyRl_l clone (A), IFNyRl_2 clone (B), IFNyRl_3 clone (C) and IFNyRl_5 clone (D). The response was compared to recombinant human IFNy (dashed black line) and FAP-IFNy (P1AF3574; light grey dashed line).

[0042] Figure 8. Comparison of EC50 values of IFNy agonistic heavy chain antibodies. EC50 values were derived from HEK-Blue assays using GraphPad Prism software (Figure 7). Values are depicted in nanomolar concentration, with recombinant human IFNy highlighted as reference (dotted line).

[0043] Figure 9. Characterization of dose-dependent response of IL-2R agonistic heavy chain antibodies. Previously identified IL-2R agonists (Figure 6B, Table 2) were screened for dose-dependent IL-2R agonism in HEK-Blue IL-2 cells. Anti-PD1-IL2v (P1AE4422) was used as reference molecule and each molecule was incubated with reporter cells at the following concentrations: 20 nM, 0.8 nM, 0.032 nM shown from left to right. IL-2R activity was quantified by absorbance at 650 nm; mean values of three technical replicates are shown, with error bars representing standard deviation.

[0044] Figure 10. MHC-I and PD-L1 expression on tumor cells after 72 hours of treatment with IFNy agonists. Previously identified IFNyR agonists (P1AH1877-P1AH1890) and control molecules (recombinant human IFNy and FAP-IFNy) were incubated with tumor cells at the following treatment concentrations: 100, 10, 1 and 0.1 nM, shown from left to right for each treatment. Measurements were subtracted by blank and normalized to the recombinant human IFNy response at the highest concentration (100 nM). Reactions are depicted for MHC-I expression on MKN45 cells (A), PD-L1 expression on MKN45 cells (B), MHC-I expression on Bxpc3 cells (C), PD-L1 expression on Bxpc3 cells (D), MHC-I expression on CorL105 cells (E) and PD-L1 expression on CorL105 cells (F).

[0045] Figure 11. Concept of split dual-targeting IFNyR agonists. FAP-dependent bi-paratopic assembly of split IFNy mimics (A). Note that for illustrative simplicity, only one monomer of the FAP dimer is represented in the insets. VHH domains with specificity for IFNyRl and IFNyR2 are fused via VH or VL fusion points to the N-termini of two different anti-FAP binding domains, resulting in eight configurations within the paratope space: IFNyRl-VHH fused to VH of FAP binder 1 (B), IFNyR2-VHH fused to VH of FAP binder 2 (C), IFNyRl-VHH fused to VL of FAP binder 1 (D), IFNyR2-VHH fused to VL of FAP binder 2 (E), IFNyR2-VHH fused to VH of FAP binder 1 (F), IFNyRl-VHH fused to VH of FAP binder 2 (G), IFNyR2-VHH fused to VL of FAP binder 1 (H), and IFNyRl-VHH fused to VL of FAP binder 2 (I). All molecules have the same Fc properties as described in Figure 5.

[0046] Figure 12. Assessment of IFNyR activity mediated by FAP-dependent split IFNyR agonists. Eight split IFNy mimics (Figure 11B-I) were paired in bi-paratopic assemblies and tested for IFNyR agonism characterized by upregulation of MHC-I and PD-L1. FAP-negative A549 cells were tested for non-targeted, non-specific MHC-I (A, B) and PD-L1 upregulation (C, D) by split IFNy mimics. A549 FAP-positive cells were co-cultured with differentially labeled A549 FAP-negative cells to assess the cis- and trans-FAP-dependent activity of IFNy mimics: cis-MHC-I upregulation (E and F), cis-PD-L1 upregulation (G and H), trans-MHC-I upregulation (I and J), and trans-PD-L1 upregulation (K and L). Recombinant IFNy and IFNy-agonistic heavy chain antibody P1AH1884 (as depicted in Figure 5) were used as references. Median fluorescence intensity (MFI) of MHC-I and PD-L1 expression levels were analyzed in FlowJo; mean values of two technical replicates are shown, with error bars representing standard deviation.

[0047] Figure 13. Additional formats of split dual-targeting IFNyR agonists. VHH domains with specificity for IFNyRl and IFNyR2 are distanced from the anti-FAP binder via N-terminal fusion to opposite Fc chains, resulting in four configurations: IFNyRl and FAP binder 1 (A), IFNyR2 and FAP binder 2 (B), IFNyR2 and FAP binder 1 (C), and IFNyRl and FAP binder 2 (D). Alternatively, VHH domains with specificity for IFNyRl and IFNyR2 are distanced from the anti-FAP binder via C-terminal fusion to the same Fc chain, resulting in four configurations: IFNyRl and FAP binder 1 (E), IFNyR2 and FAP binder 2 (F), IFNyR2 and FAP binder 1 (G), and IFNyRl and FAP binder 2 (H). Anti-FAP binders in Figure 13E-13H include CrossFab VH / VL engineering (binder 1) and CH1-CL charge (binder 2) to subsequently allow additional pairing. All molecules have the same Fc properties as described in Figure 5.

[0048] Figure 14. Assessment of IFNyR activity mediated by additional FAP-dependent split IFNyR agonists. Four combinations of molecules depicted in Figure 13 and control molecules were tested for IFNyR agonism characterized by upregulation of MHC-I and PD-L1. A549 cells lacking FAP expression were tested for FAP-independent MHC-I upregulation (A) and PD-L1 upregulation (B) of split IFNy mimics. A549 FAP-positive cells were co-cultured with differentially labeled A549 FAP-negative cells to assess FAP-dependent activity of IFNy mimics by cis MHC-I upregulation (C), cis PD-L1 upregulation (D), trans MHC-I upregulation (E), and trans PD-L1 upregulation (F). Recombinant IFNy and IFNy agonistic heavy chain antibody (P1AH1884) were used as reference molecules. Median fluorescence intensity (MFI) of MHC-I and PD-L1 expression levels were analyzed in FlowJo; mean values of two technical replicates are shown, with error bars representing standard deviation.

[0049] Figure 15. Concept of split IFNy agonists targeting FAP with different linker lengths. Within the antibody construct containing a FAP-binding Fab domain, a single VHH domain with specificity for either IFNyRl or IFNyR2 was engineered to connect to the hinge region at the N-terminus of the Fc region (top row) or to the C-terminus of the Fc region (bottom row). The construct utilizes one of the two different FAP-binding Fab domains that do not compete for binding. Flexible linkers consisting of 5, 15, or 25 amino acids (indicated by the number after the semicolon following the molecule ID) were used to connect the Fc region to the VHH domain. This resulted in a series of 24 unique configurations that can be paired to yield 12 functional IFNy agonists targeting FAP: P1AJ8564 + P1AJ8567, P1AJ8560 + P1AJ8563, and P1AJ8568 + P1AJ8571 (A); P1AJ8566 + P1AJ8565, P1AJ8562 + P1AJ8561, and P1AJ8570 + P1AJ8569 (B); P1AJ8576 + P1AJ8579, P1AI0187 + P1AJ8575, and P1AJ8580 + P1AJ8583 (C); P1AJ8578 + P1AJ8577, P1AJ8574 + P1AJ8573, and P1AJ8582 + P1AJ8581 (C).

[0050] Figure 16. Assessment of IFNyR activity mediated by additional FAP-dependent split IFNyR agonists. Twelve combinations of the molecules depicted in Figure 15 and control molecules were tested for IFNyR agonism characterized by MHC-I upregulation. Test compounds were incubated with A549 FAP-negative cells alone (non-targeting condition; A and D), or with a combination of the A549 FAP-negative cells and A549 FAP-positive cells, where both cis-signaling (FAP binding on A549 FAP-positive cells and activity on A549 FAP-positive cells; B and E) and trans-signaling (FAP binding on A549 FAP-positive cells and activity on A549 FAP-negative cells, C and F) were assessed. Recombinant IFNy and the IFNy-agonistic heavy chain antibody (P1AH1884) were used as reference molecules. Median fluorescence intensity (MFI) of MHC-I expression levels was analyzed in FlowJo; mean values of two technical replicates are shown, with error bars representing standard deviation.

[0051] Figure 17. Concept of split IFNy agonists targeting EGFR. VHH domains with specificity for IFNyRl and IFNyR2 are fused via the VH or VL fusion point to the N-terminus of two different anti-EGFR binding domains, resulting in eight individual format configurations (P1AK5514 - P1AK5521), which can be paired to generate the eight functional assemblies depicted: P1AK5520 + P1AK5519 (A), P1AK5516 + P1AK5515 (B), P1AK5521 + P1AK5518 (C), P1AK5517 + P1AK5514 (D), P1AK5520 + P1AK5515 (E), P1AK5516 + P1AK5519 (F), P1AK5521 + P1AK5514 (G), and P1AK5517 + P1AK5518 (H).

[0052] Figure 18. Functional activity of IFNy agonists targeting EGFR. Test compounds were incubated with target cells as well as PBMCs, and CXCL10 production was assessed after 24 hours of stimulation. Recombinant IFNy was used as a reference. Mean values + / - SD of two technical replicates per concentration of test molecule are shown.

[0053] Figure 19. Concept of split dual-targeting IL-2 agonists. PD-1 dependent dual-paratope assembly of split IL-2 mimics (A). VHH domains with specificity for IL-2Rß and IL-2Ry are fused via the VH or VL fusion point to the N-terminus of two different anti-PD-1 binding domains: IL-2Rß-VHH fused to VH of PD-1 binder 1 (B), IL-2Ry-VHH fused to VL of PD-1 binder 2 (C), IL-2Rß-VHH fused to VL of PD-1 binder 1 (D), and IL-2Ry-VHH fused to VH of PD-1 binder 2 (E). IL-2 agonistic heavy chain antibodies (F) and PD-1-IL2v (G) serve as reference molecules. All molecules have the same Fc properties as described in Figure 5.

[0054] Figure 20. Phosphorylation of STAT5 on CD4 T cells after 15 minutes and 60 minutes of incubation with IL-2R agonists. Activated T cells expressing PD-1 (PD-1 +and activated T cells pre-blocked with anti-PD-1 antibody (PD-1 - Differentially labeled and treated with two combinations of split bi- targeting IL-2 mimics: P1 AH6850 + P1 AH6813 (A-D), P1 AH6814 + P1 AI1593 (E-H). IL-2 mimicking heavy chain antibody (P1 AH1177) and PD1-IL2v (P1 AE4422) were used as reference molecules. STAT5-P + MFI and frequency of cells were measured by FACS and showed the response of PD-1 + subset (solid line) and PD-1 - subset (dashed line).

[0055] Figure 21. Flow cytometry gating strategy and baseline receptor expression. Isolated PBMC from two healthy donors were stained with viability dye and fluorescent dye-conjugated antibodies against cell surface antigens. Gating strategy to identify five different cell types: NK cells and NKT cells (A); CD4 T cells and CD8 T cells (B); and gd T cells (C). Representative plots showing PD-1 and IL-2R co-expression on CD8 T cells (D), gd T cells (E) and NK cells (F).

[0056] Figure 22. CD25 expression on PBMC subsets induced by PD-1 -targeting IL-2R agonists. Frequency of CD25 expressing CD8 T cells (A), gd T cells (B) and NK cells (C) was determined by flow cytometry after five days of test compounds co-incubation with freshly isolated CTV-labeled PBMCs. PD1-IL2v (P1 AE4422) and Fc-VHH (P1 AH1177) were used as controls. Non-binding DP47 antibody (P1 AD3966) was used as negative control. Mean values + / - SEM of two PBMC donors in combination and two technical replicates for each test molecule concentration are shown.

[0057] Figure 23. Proliferation of PBMC subsets induced by IL-2R agonists targeting PD-1. The frequency of proliferating CD8 T cells (A), gd T cells (B) and NK cells (C) was determined by flow cytometry after five days of incubation of test compounds with freshly isolated CTV-labeled PBMCs. Proliferating cells were identified according to cell division visualized with CTV staining. PD1-IL2v (P1AE4422) and Fc-VHH (P1AH1177) were used as controls. Non-binding DP47 antibody (P1AD3966) was used as negative control. Mean values + / - SEM of two PBMC donors combined and two technical replicates per concentration of each test molecule are shown.

[0058] Figure 24. Presentation of results of experiments evaluating the effectiveness of the combination of IL-2R agonists targeting PD-1 (P1AI1593 and P1AH6814), PD1-IL2v immunoconjugate (P1AE4422) and pembrolizumab with FOLR1-TCB Mab. BC004 human breast cancer PDX cells were injected into the intramammary fat pad of humanized BRGS47 mice to study tumor growth inhibition in a breast orthotopic xenograft model. The amount of antibody injected per mouse (mg / kg) was as follows: P1AI1593, P1AH6814 and pembrolizumab 1 mg / kg; PD1-IL2v 0.1 mg / kg; and FOLR1-TCB 0.3 mg / kg. Antibodies were injected intravenously once a week for 4 weeks. The combination of FOLR1-TCB 0.3 mg / kg + IL-2R agonists targeting PD1 (P1AI1593 day 1 + P1AH6814 day 2) mediated superior efficacy in inhibiting tumor growth over FOLR1-TCB monotherapy treatment and the following other combination groups: FOLR1-TCB 0.3 mg / kg + PD1-IL2v and FOLR1-TCB 0.3 mg / kg + pembrolizumab.

[0059] Figure 25. Concept of split IL-2R agonists targeting PD-1 with alternative anti-PD-1 Fab binders. VHH domains with specificity for IL-2Rß and IL-2Ry were fused via VH or VL fusion points to the N-terminus of two different anti-PD-1 binding domains, resulting in eight individual format configurations (P1AK2599; P1AK2798; P1AK2799; P1AK2802; P1AK2803; P1AK2806; P1AK2809; P1AK2810), which can be paired to generate the eight functional assemblies depicted: P1AK2802 + P1AK2599 (A), P1AK2809 + P1AK2799 (B), P1AK2803 + P1AK2806 (C), P1AK2810 + P1AK2798 (D), P1AK2809 + P1AK2599 (E), P1AK2802 P1AK2799 (F), P1AK2810 + P1AK2806 (G), and P1AK2803 + P1AK2798 (H).

[0060] Figure 26. Functional activity of IL-2R agonists targeting PD-1 with alternative anti-PD-1 Fab binders. Test compounds were incubated with HEK Blue IL-2 wt cells (A) or HEK Blue IL-2 human PD-1 cells (B) for 21 hours at 37°C and 5% CO2. PD1-IL2v (P1AE4422) and Fc-VHH (P1AH1177) were used as controls. Non-binding DP47 antibody (P1AD3966) was used as negative control. IL-2R signaling was measured via absorbance at 650 nm using QUANTI-Blue reagent. Mean absorbance values + / - SEM of two technical replicates per test molecule concentration are shown.

[0061] Figure 27. Concept of split IL-2R agonists targeting LAG-3. VHH domains with specificity for IL-2Rβ and IL-2Rγ were fused via VH or VL fusion points to the N-terminus of two different anti-LAG-3 binding domains, resulting in eight individual format configurations (P1AJ5654 - P1AJ5661), which can be paired to generate the eight functional assemblies depicted: P1AJ5654 + P1AJ5661 (A), P1AJ5658 + P1AJ5657 (B), P1AJ5655 + P1AJ5660 (C), P1AJ5659 + P1AJ5656 (D), P1AJ5658 + P1AJ5661 (E), P1AJ5654 + P1AJ5657 (F), P1AJ5659 (G), and P1AJ5655 + P1AJ5656 (H).

[0062] Figure 28. Functional activity of IL-2R agonists targeting LAG-3. PD1-IL2v (P1AE4422) and Fc-VHH (P1AH1177) were used as controls. Frequency (A) and MFI (B) of STAT-5 phosphorylation were determined by flow cytometry after 60 minutes of co-incubation of test compounds with CD4 T cells pre-activated for three days with plate-bound anti-CD3 and soluble anti-CD28 antibodies.

[0063] Figure 29. Concept of split IL-2R agonists targeting FAP. VHH domains with specificity for IL-2Rβ and IL-2Rγ were fused via VH or VL fusion points to the N-terminus of two different anti-FAP binding domains, resulting in eight individual format configurations (P1AJ5092 - P1AJ5099), which can be paired to generate the eight functional assemblies depicted: P1AJ5096 + P1AJ5099 (A), P1AJ5092 + P1AJ5095 (B), P1AJ5097 + P1AJ5098 (C), P1AJ5093 + P1AJ5094 (D), P1AJ5096 + P1AJ5095 (E), P1AJ5092 + P1AJ5099 (F), P1AJ5097 + P1AJ5094 (G), and P1AJ5093 + P1AJ5098 (H).

[0064] Figure 30. Functional activity of FAP-targeted IL-2R agonists. Test compounds were incubated with A549 FAP-negative target cells (A) or A549 FAP-positive target cells (B) and IL-2Rβγ bioassay cells for 20 hours at 37°C and 5% CO2. PD1-IL2v (P1AE4422), FAP-IL2v (P1AA5355), and Fc-VHH (P1AH1177) were used as controls. Non-binding DP47 antibody (P1AD3966) was used as a negative control. IL-2R signaling was measured via luminescence using Bio-Glo NL reagent and normalized to background signal. Mean fold change RLU values + / - SEM of two technical replicates per test molecule concentration are shown.

[0065] Figure 31. Concept of split IL-2R agonists targeting EGFR. VHH domains with specificity for IL-2Rβ and IL-2Rγ were fused via VH or VL fusion points to the N-terminus of two different anti-EGFR binding domains, resulting in eight individual format configurations (P1AJ4165 - P1AJ4172), which can be paired to generate the eight functional assemblies depicted: P1AJ4169 + P1AJ4172 (A), P1AJ4165 + P1AJ4168 (B), P1AJ4170 + P1AJ4171 (C), P1AJ4166 + P1AJ4167 (D), P1AJ4169 + P1AJ4168 (E), P1AJ4165 + P1AJ4172 (F), P1AJ4170 + P1AJ4167 (G), and P1AJ4166 + P1AJ4171 (H).

[0066] Figure 32. Functional activity of IL-2R agonists targeting EGFR. EGFR expression on target cells (A) by flow cytometry. Test compounds were incubated with A431 target cells (B), OE19 target cells (C) or LoVo target cells (D) and IL-2Rβγ bioassay cells for 20 hours at 37°C and 5% CO2. PD1-IL2v (P1AE4422) and Fc-VHH (P1AH1177) were used as controls. Non-binding DP47 antibody (P1AD3966) was used as negative control. IL-2R signaling was measured via luminescence using Bio-Glo NL reagent and normalized to background signal. Mean fold change RLU values + / - SEM of two technical replicates per test molecule concentration are shown.

[0067] Figure 33. Concept of split IL-2R agonists targeting HER2 and HER3. VHH domains with specificity for IL-2Rβ and IL-2Rγ were fused to the N-terminus of two different anti-HER2 binding domains and two different anti-HER3 binding domains. The VH or VL fusion point was chosen for each Fab according to structural data. Four format configurations (P1AJ4173 - P1AJ4176) and two paired assemblies were designed for HER2: P1AJ4174 + P1AJ4175 (A) and P1AJ4173 + P1AJ4176 (B). Four format configurations (P1AJ4177 - P1AJ4180) and two paired assemblies were chosen for HER3: P1AJ4178 + P1AJ4179 (C) and P1AJ4177 + P1AJ4180 (D).

[0068] Figure 34. Functional activity of IL-2R agonists targeting HER2 and HER3. Test compounds were incubated with MDA-MB-231 target cells (A) or OE19 target cells (B) and IL-2Rβγ bioassay cells for 20 hours at 37°C and 5% CO2. PD1-IL2v (P1AE4422) and Fc-VHH (P1AH1177) were used as controls. Non-binding DP47 antibody (P1AD3966) was used as negative control. IL-2R signaling was measured via luminescence using Bio-Glo NL reagent and normalized to background signal. Mean fold change RLU values + / - SEM of two technical replicates per test molecule concentration are shown.

[0069] Figure 35. Concept of split IL-2R agonists targeting PD-1 with alternative anti-PD-1 single domain binders. VHH domains with specificity for IL-2Rß and IL-2Ry were fused to the N-terminus of four different anti-PD-1 single domain binders (P1AI0063; P1AK3046; P1AK3048; P1AK3051 - P1AK3054) that can pair to generate the six functional assemblies depicted: P1AK3052 + P1AK3048 (A), P1AI0063 + P1AK3051 (B), P1AK6054 + P1AK3048 (C), P1AI0063 + P1AK3053 (D), P1AK3054 + P1AK3046 (E), and P1AK3052 + P1AK3046 (F).

[0070] Figure 36. Functional activity of IL-2R agonists targeting PD-1 with alternative anti-PD-1 single domain binders. Test compounds were incubated with HEK Blue IL-2 wt cells (A) or HEK Blue IL-2 human PD-1 cells (B) for 20 hours at 37°C and 5% CO2. PD1-IL2v (P1AE4422) and Fc-VHH (P1AH1177) were used as controls. Non-binding DP47 antibody (P1AD3966) was used as negative control. IL-2R signaling was measured via absorbance at 650 nm using QUANTI-Blue reagent. Mean absorbance values + / - SEM of two technical replicates per test molecule concentration are shown.

[0071] Figure 37. Concept of split IL-2R agonists targeting PD-1 with anti-IL2R Fab binders or anti-IL2R scFv binders. Fab fragments with IL-2Rß and IL-2Ry specificity are fused via the VH or VL fusion point to the N-terminus of two anti-PD1 binding domains with different paratopes. P1AL9238 (A) and P1AL9239 (B) contain PD1 binder 2 (FV003451 paratope; 1040 binder) and two different IL2Ry binders FV018863 and FV018864, respectively, while P1AL9240 (C) and P1AL9241 (D) contain PD1 binder 1 (FV000363 paratope; 0376 binder) and two different IL2Rp binders FV002203 and FV018866, respectively. These can be paired to generate four functional assemblies: P1AL9238 + P1AL9240, P1AL9238 + P1AL9241, P1AL9239 + P1AL9240, P1AL9239 + P1AL9241. Alternatively, scFv fragments with IL-2Rp and IL-2Ry specificity are fused via the VH or VL fusion point to the N-terminus of two anti-PD1 binding domains with different paratopes. P1AL9310 (E) contains PD1 binder 2 (FV003451 paratope) and IL2Ry binder FV018865, while P1AL9311 (F) contains PD1 binder 1 (FV000363 paratope) and IL2Rp binder FV018866. These can be paired to generate a functional assembly: P1AL9310 + P1AL9311.

[0072] Figure 38. Functional activity of PD-1 -targeted IL-2R agonists with anti-IL2R Fab and scFv binders. Test compounds were incubated with HEK Blue IL-2 wt cells (A) or HEK Blue IL-2 human PD-1 cells (B) for 18 hours at 37°C and 5% CO2. IL-2 agonistic heavy chain antibody (Fc-VHH; P1 AH1177) was used as a control. Non-binding DP47 antibody (P1 AD3966) was used as a negative control. IL-2R signaling was measured via absorbance at 650 nm using QUANTI-Blue reagent. Fold change in IL-2R signaling over background + / - SEM is shown for two technical replicates per test molecule concentration.

[0073] Figure 39. Schematic representation of antigens and workflow for isolation of IL-7Ra- specific single domain antibodies. Extracellular domain (ECD) of human IL-7Ra (P1 AI1009 represented in A) was generated for llama immunization, phage display and screening with biotinylated Fc knob-into-hole fusion. Soluble human Fc knob-into-hole (P1 AD4290 represented in B) was generated for phage display. Workflow for enrichment of single domain antibodies with binding specificity for IL-7Ra by phage display (C).

[0074] Figure 40. Specific screening of single domain antibodies by ELISA. Soluble VHH domains enriched for IL-7Ra specificity were randomly selected and screened for binding to immobilized human IL-7Ra-Fc and immobilized human Fc. VHHs from library 1 (A) and library 2 (B) were tested for antigen specificity after three rounds of phage display. Enriched VHHs from library 1 (C) and library 2 (D) were also tested for specificity by ELISA after four rounds. Absorbance at 450 nm indicative of binding response to each target is represented as stacked bar graphs.

[0075] Figure 41. Conversion of single-domain antibody fragment formats into bispecific heavy chain antibodies. Round 3 and Round 4 IL-7Ra-specific VHHs from libraries 1 and 2 were fused to Fc knobs and cloned into mammalian cell expression vectors using Gibson cloning (A). Previously identified VHHs with IL-2Ry specificity were fused to Fc knobs using the same approach (B). Bispecific heavy chain antibodies comprising IL-7Ra-IL-2Ry VHH domain pairs were generated via knob-into-hole assembly of Fc chains and flexible 5 (G4S) linkers to fuse the VHH moieties to the Fc chains. Effector function of the Fc was silenced via incorporation of a P329G LALA mutation in the CH2 domain (C).

[0076] Figure 42. Functional characterization of dose-dependent responses of IL-7R agonists. Bispecific heavy chain antibodies comprising IL-7Ra-specificity and IL-2Ry were screened for dose-dependent IL-7R agonism in HEK Blue IL-7 cells. Recombinant IL-7 was used as a reference, and an IgG with an irrelevant specificity was used as a negative control (P1AA5879). Each molecule was incubated with reporter cells at the following concentrations: 20 nM, 2 nM, 0.2 nM, 0.02 nM from left to right. IL-7R activity was quantified by absorbance at 650 nm, and the fold of response per background is shown for each treatment. The panel is separated according to four different IL-2Ry-specific VHH clones: IL2Ry_2 (A), IL2Ry_3 (B), IL2Ry_4 (C), and IL2Ry_5 (D).

[0077] Figure 43. Concept of split IL-7R agonists targeting PD-1. PD-1-dependent bicomplementarity site assembly of split IL-7 mimics (A). VHH domains with IL-7Ra and IL-2Ry specificity were fused via VH or VL fusion points to the N-terminus of two different anti-PD-1 binding domains: IL-7Ra-VHH was fused to the VL of PD-1 binder 1 (B), and IL-2Ry-VHH was fused to the VH of PD-1 binder 2 (C). IL-7Ra molecules contain AAA mutations (I253A; H310A; H435A, numbering according to Kabat EU index) in the CH2 and CH3 domains of the Fc knob to facilitate protein A purification. Effector function of the Fc was silenced in all molecules via incorporation of a P329G LALA mutation in the CH2 domain.

[0078] Figure 44. Functional activity of IL-7R agonists targeting PD-1. PD1-IL2v (P1AE4422) and Fc-VHH (P1AH1177) were used as controls. Non-binding DP47 antibody (P1AD3966) was used as negative control. Frequency of STAT-5 phosphorylation was determined by flow cytometry after 60 minutes of co-incubation of test compounds with plate-bound anti-CD3 and soluble anti-CD28 antibodies pre-activated CD4 T cells for three days from blood donor 1 (A and B) and 2 (C and D).

[0079] Figure 45. Concept of split IL-2R agonists targeting PD-1 single paratope assembly onto PD-1. VHH domains with specificity for IL-2Rβ and IL-2Rγ were fused via VH or VL fusion points to the N-terminus of two different anti-PD-1 binding domains, resulting in eight separate format configurations of IL-2R agonist pairs containing identical anti-PD-1 Fab binders (single paratope assembly) that can pair to generate eight single paratope assemblies: P1AK2802 + P1AK2810 (A), P1AK2809 + P1AK2803 (B), P1AK2802 + P1AK2803 (C), P1AK2809 + P1AK2810 (D), P1AK2798 + P1AK2599 (E), P1AK2806 + P1AK2799 (F), P1AK2798 + P1AK2799 (G), and P1AK2806 + P1AK2599 (G).

[0080] Figure 46. Functional activity of mono- versus bi-paratope targeting PD-1 IL-2R agonists. Test compounds were incubated with HEK Blue IL-2wt (A) or HEK Blue IL-2 human PD-1 cells (B) for 21 hours at 37°C and 5% CO2. Two bi-paratope targeting PD-1 IL-2R agonists (P1AH6814 + P1AI1593 and P1AH6814 + P1AK2802) and an IL-2 mimicking heavy chain antibody (Fc-VHH; P1AH1177) were used as reference. A non-binding DP47 antibody (P1AD3966) was used as negative control. IL-2R signaling was measured via absorbance at 650 nm using QUANTI-Blue reagent. Mean absorbance values + / - SEM of two technical replicates per test molecule concentration are shown. DETAILED DESCRIPTION

[0081] Definitions

[0082] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The methods and techniques of the present disclosure are generally performed according to conventional methods well-known in the art. Generally, nomenclatures used in connection with, and techniques of, biochemical, enzymatic, molecular, and cellular biology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art.

[0083] The terms "a," "an," "the" generally include plural references unless the context clearly dictates otherwise.

[0084] As used herein, the terms "first," "second," "third," or "fourth" in reference to binding molecules, epitopes, polypeptides, etc. are used to conveniently distinguish between more than one of each type of moiety. The use of these terms is not intended to confer a particular order or orientation to the moieties unless explicitly stated.

[0085] As used herein, the term "antigen binding molecule" refers to a polypeptide molecule (composed of one or more polypeptide chains) that is capable of binding to an antigen. An antigen binding molecule can be derived from an antibody, and typically comprises an antigen binding domain.

[0086] The term "antibody" herein is used in the broadest sense and includes various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), heavy chain antibodies, antibody fragments, and antigen binding molecules so long as they exhibit the desired antigen-binding activity.

[0087] The terms "heavy chain antibody" and "heavy chain only antibody" and "HCAb" as used herein refer to antibodies that do not contain light chains.

[0088] The terms "full-length antibody," "intact antibody," and "whole antibody" are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure.

[0089] "Antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, cross-Fab, Fab', Fab'-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv and scFab), single-domain antibodies, and multispecific antibodies formed from antibody fragments. For a review of certain antibody fragments, see Hollinger and Hudson, Nature Biotechnology 23:1126-1136 (2005).

[0090] "Single-domain antibody" refers to an antibody fragment consisting of a single monomeric variable domain such as VHH, nanobody, VNAR derived from sharks, an autonomous VH domain, or an autonomous VL domain. A single-domain antibody provides an antigen binding site that specifically binds to an epitope, i.e., the antigen binding site is formed solely by the single-domain antibody.

[0091] "VHH" or "VHH domain" or "nanobody" refers to a single-domain antibody derived from the variable domain of a heavy chain antibody from Camelidae, e.g., camel, dromedary, llama, alpaca, and the like (see Nguyen V.K. et al., 2000, The EMBO Journal, 19, 921-930; Muyldermans S., 2001, J Biotechnol., 74, 277-302 and for review see Vanlandschoot P et al., 2011, Antiviral Research 92, 389-407). The antigen binding site of a VHH lacks a light chain variable domain. The VHH domain can be humanized.

[0092] As used herein, an “antigen binding domain” refers to a domain that specifically binds to a target antigen. The term specifically refers to an antigen binding domain of an antibody, i.e., a moiety comprising a region that binds to and is complementary to part or all of an antigen. Thus, in particular aspects, an antigen binding domain herein is an antigen binding domain of an antibody. Such an antigen binding domain can be provided by an antibody fragment, e.g., by a Fab molecule, a single chain antibody molecule, or a single domain antibody such as a VHH domain.

[0093] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The term encompasses VHH domains. The variable regions of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, with each domain comprising four conserved framework regions (FRs) and complementary determining regions (CDRs). See, e.g., Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman & Co., page 91 (2007). A single VH or VL domain can be sufficient to confer antigen-binding specificity. Furthermore, an antibody that binds a particular antigen can be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991). As used herein in connection with variable region sequences, “Kabat numbering” refers to the numbering system set forth by Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991).

[0094] As used herein, the amino acid positions of all constant regions and constant domains of heavy and light chains are numbered according to the Kabat numbering system described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991), and are referred to herein as “according to Kabat numbering” or “Kabat numbering.”

[0095] In particular, the Kabat numbering system (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) pp. 647-660) is used for the light chain constant domains CL of the kappa and lambda isotypes, and the Kabat EU index numbering system (see pp. 661-723) is used for the heavy chain constant domains (CH1, hinge, CH2 and CH3), which is further elucidated herein by referring in such case to “numbering according to Kabat EU index” or “Kabat EU index numbering”.

[0096] As used herein, the term “binding site” or “antigen binding site” refers to the site of a binding molecule, i.e. one or more amino acid residues, that provides for the interaction with an antigen. For example, an antigen binding site of an antigen binding domain comprises amino acid residues from complementarity determining regions (CDRs). An antigen binding site can be provided by, e.g., one or more variable domains (also referred to as variable regions). In a single domain antibody, the antigen binding site is provided by a single variable domain. While in a Fab fragment, the antigen binding site is provided by the VH and VL domains.

[0097] As used herein, the term “hypervariable region” or “HVR” refers to each of the regions of an antigen binding domain that are highly variable in sequence and that determine antigen binding specificity, e.g., “complementarity determining regions” (“CDRs”). Generally, a variable domain includes three CDRs. Thus, an antibody comprising VH and VL includes six CDRs; three in the VH (HCDR1, HCDR2, HCDR3) and three in the VL (LCDR1, LCDR2, LCDR3). Exemplary CDRs herein include:

[0098] (a) the hypervariable loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)) that occur at amino acid residues 26-32 (L1 ), 50-52 (L2), 91-96 (L3), 26-32 (H1 ), 53-55 (H2), and 96-101 (H3);

[0099] (b) CDRs that occur at amino acid residues 24-34 (LI), 50-56 (L2), 89-97 (L3), 31-35b (HI), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)) and

[0100] (c) antigen contacts that occur at amino acid residues 27c-36 (LI), 46-55 (L2), 89-96 (L3), 30-35b (HI), 47-58 (H2), and 93-101 (H3) (MacCallum et al., J. Mol. Biol. 262:732-745 (1996)).

[0101] Unless otherwise indicated, CDRs are determined according to the method described by Kabat et al., supra. Those skilled in the art will appreciate that CDR designations can also be determined according to the methods described by Chothia, supra, McCallum, supra, or any other scientifically accepted nomenclature system.

[0102] “Framework” or “FR” refers to variable domain residues other than complementary determining regions (CDRs). The FRs of a variable domain generally consist of four FR domains: FR1, FR2, FR3, and FR4. Thus, HVR sequences and FR sequences generally appear in the following order in VH and VHH domains (or VL): FR1-HCDR1 (LCDR1)-FR2-HCDR2 (LCDR2)-FR3-HCDR3 (LCDR3)-FR4. Unless otherwise indicated, CDR residues and other residues in a variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0103] The term "immunoglobulin molecule" herein refers to a protein having the structure of a naturally occurring antibody. For example, an IgG class immunoglobulin is a heterotetrameric glycoprotein of about 150,000 Daltons, composed of two light chains and two heavy chains that are linked by disulfide bonds. From N- to C-terminus, each heavy chain has a variable domain (VH) (also called variable heavy domain or heavy chain variable region), followed by three constant domains (CHI, CH2, and CH3) (also called heavy chain constant region). Similarly, from N- to C-terminus, each light chain has a variable domain (VL) (also called variable light domain or light chain variable region), followed by a constant light (CL) domain (also called light chain constant region). The heavy chains of an immunoglobulin can be assigned to one of five types, called α (IgA), δ (IgD), ε (IgE), γ (IgG), or μ (IgM), some of which can be further divided into subtypes, e.g., γ1 (IgG1), γ2 (IgG2), γ3 (IgG3), γ4 (IgG4), α1 (IgA1), and α2 (IgA2). The light chains of an immunoglobulin can be assigned to one of two types based on the amino acid sequence of their constant domains: called kappa (K) and lambda (λ). An immunoglobulin is essentially composed of two Fab molecules and one Fc domain connected by an immunoglobulin hinge region.

[0104] The "class" of an antibody or immunoglobulin refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes) e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0105] A "Fab molecule" or "Fab" or "Fab fragment" or "Fab domain" refers to a protein composed of the VH and CHI domains of a heavy chain ("Fab heavy chain") of an immunoglobulin and the VL and CL domains of a light chain ("Fab light chain").

[0106] A "cross-Fab molecule" or "cross-Fab" or "cross-Fab molecule" refers to a Fab molecule in which the variable or constant regions of the heavy and light chains are exchanged. Cross-Fab engineering enables two different chain compositions of the cross-Fab molecule. In one aspect, the variable regions of the Fab heavy and light chains are exchanged, i.e. the cross-Fab molecule comprises a peptide chain consisting of a light chain variable region (VL) and a heavy chain constant region (CH1), wherein CH1 can be fused to a Fc domain, and a peptide chain consisting of a heavy chain variable region (VH) and a light chain constant region (CL). In another aspect, when the constant regions of the Fab heavy and light chains are exchanged, the cross-Fab molecule comprises a peptide chain consisting of a heavy chain variable region (VH) and a light chain constant region (CL), wherein CL can be fused to a Fc domain, and a peptide chain consisting of a light chain variable region (VL) and a heavy chain constant region (CH1).

[0107] The term "conventional Fab molecule" refers to a Fab molecule composed of a Fab heavy chain comprising a VH and a CH1 domain and a Fab light chain comprising a VL and a CL domain.

[0108] A "single-chain variable fragment" or "scFv" molecule is a fusion protein of a heavy chain variable domain (VH) and a light chain variable domain (VL) of an antibody connected by a linker. In particular, the linker is a short polypeptide of 10 to about 25 amino acids and is typically rich in glycine for flexibility, as well as serine or threonine for solubility, and can connect the N-terminus of the VH with the C-terminus of the VL, or vice versa. Despite the removal of the constant regions and the introduction of the linker, the protein retains the specificity of the original antibody.

[0109] The term "multispecific" means that a binding molecule (e.g., an antibody) is capable of specific binding to at least two different antigens. A multispecific binding molecule (e.g., an antibody) can be, for example, a bispecific binding molecule. Typically, a bispecific binding molecule comprises two antigen binding sites, each of which is specific for a different antigen. In certain aspects, a multispecific (e.g., bispecific) binding molecule is capable of simultaneously binding two antigens, particularly two antigens expressed on the same cell, on adjacent cells, or in the same tissue.

[0110] The term "valency" as used herein denotes the presence of a specified number of antigen binding sites in a binding molecule. Thus, the term "binds to an antigen monovalently" denotes the presence of one (and no more than one) antigen binding site in a binding molecule that is specific for an antigen.

[0111] As used herein, the term "antigen" refers to a molecule, such as a protein, that binds to an antigen binding molecule. Useful antigens can be found on the surface of, for example, tumor cells, on the surface of tumor stroma cells, on the surface of virus infected cells, on the surface of other diseased cells, on the surface of immune cells, free in serum, and / or in the extracellular matrix (ECM). In a particular aspect, the antigen is a human protein.

[0112] As used herein, the term "epitope" refers to the site on an antigen to which an antigen binding site binds. Epitopes can be formed both by contiguous amino acids or by conformational configurations of noncontiguous amino acids. Epitopes are generally composed of chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups or sulfonyl groups and can have specific three-dimensional structural characteristics, as well as specific charge characteristics. Two different antigen binding domains that are able to bind to the same antigen can bind to different epitopes of said antigen. Two different antigen binding domains are said to not compete if they can both bind to the antigen at the same time. In this case, the two different antigen binding domains are non-competitive. Alternatively, antigen binding domains can compete for binding, i.e. show competitive binding. This can be due to partly overlapping epitopes or due to steric hindrance that hinders the simultaneous binding of two antigen binding domains. Assays to determine whether an antigen binding domain shows non-competitive or competitive binding are well known in the art, e.g. competitive binding assays using ELISA, RIA, surface plasmon resonance, flow cytometry or any other quantitative or qualitative antibody binding assay available in the art.

[0113] As used herein, "target antigen" refers to an antigen present on the surface of a target cell, e.g. an antigen on a cell in a tumor, such as a cancer cell or a cell of the tumor stroma, or an antigen on a T cell.

[0114] As used herein, "tumor associated antigen" refers to any antigen present on the surface of a cell in a tumor, such as a cancer cell or a cell of the tumor stroma. Particular tumor associated antigens are CEA, FAP, Her2, Her3 or EGFR.

[0115] The term "fibroblast activation protein (FAP)" also known as prolyl endopeptidase FAP or Seprase (EC 3.4.21) refers to any native FAP from any vertebrate source, including mammals such as primates (e.g., humans) non-human primates (e.g., cynomolgus monkeys), and rodents (e.g., mice and rats), unless otherwise indicated. FAP is expressed on cancer-associated fibroblasts (CAFs) in the tumor stroma. The term encompasses "full-length," unprocessed FAP, as well as any form of FAP that results from processing in the cell. The term also encompasses naturally occurring variants of FAP, e.g., splice variants or allelic variants. In one embodiment, the antigen binding molecules of the application are capable of specifically binding to human, mouse and / or cynomolgus FAP. The amino acid sequence of human FAP is shown in UniProt (www.uniprot.org) accession no. Q12884 (version 149) or NCBI (www.ncbi.nlm.nih.gov / ) RefSeq NP_004451.2. The extracellular domain (ECD) of human FAP extends from amino acid position 26 to position 760. The amino acid sequence of mouse FAP is shown in UniProt accession no. P97321 (version 126) or NCBI RefSeq NP_032012.1. The extracellular domain (ECD) of mouse FAP extends from amino acid position 26 to amino acid position 761. Preferably, the anti-FAP binding molecules bind to the extracellular domain of FAP. Exemplary anti-FAP binding molecules are described in international patent application no. WO 2012 / 020006 A2 and WO 2020 / 070041 Al.

[0116] The term "carcinoembryonic antigen (CEA)" also known as carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), refers to any native CEA from any vertebrate source, including mammals such as primates (e.g., humans), non-human primates (e.g., cynomolgus monkeys), and rodents (e.g., mice and rats), unless otherwise indicated. The amino acid sequence of human CEA is set forth in UniProt accession no. P06731 (version 151). CEA has long been identified as a tumor-associated antigen (Gold and Freedman, J Exp Med., 121 :439-462, 1965; Berinstein N.L., J Clin Oncol., 20:2197-2207, 2002). CEA was originally classified as a protein expressed only in fetal tissues, and has now been identified in a variety of normal adult tissues. These tissues are primarily of epithelial origin, including cells of the gastrointestinal, respiratory, and urogenital tracts, as well as cells of the colon, cervix, sweat glands, and prostate (Nap et al., Tumour Biol., 9(2-3): 145-53, 1988; Nap et al., Cancer Res., 52(8):2329-23339, 1992). Tumors of epithelial origin and their metastases both comprise CEA as a tumor-associated antigen. The presence of CEA itself does not indicate that a cell has been transformed into a cancer cell, but the distribution of CEA is indicative. In normal tissues, CEA is usually expressed on the apical surface of cells (Hammarström S., Semin Cancer Biol. 9(2):67-81 (1999)), making it inaccessible to antibodies in the bloodstream. In contrast to normal tissues, CEA tends to be expressed on the entire surface of cancer cells (Hammarström S., Semin Cancer Biol. 9(2):67-81 (1999)). This change in expression pattern makes CEA accessible for binding to antibodies in cancer cells. Furthermore, CEA is increased in expression in cancer cells. In addition, the increased expression of CEA promotes an increase in cell-cell adhesion, which can lead to metastasis (Marshall J., Semin Oncol., 30(a Suppl. 8):30-6, 2003). Expression of CEA is generally very high in various tumor entities.According to published data, analyses performed by the authors on their own organization samples confirmed the high incidence of CEA, with an incidence of about 95% in colorectal cancer (CRC), 90% in pancreatic cancer, 80% in gastric cancer, 60% in non-small cell lung cancer (NSCLC, co-expressed with HER3), 40% in breast cancer; and low expression levels were found in small cell lung cancer and glioblastoma.

[0117] “HER2” (also known as erbB-2 or CD340) refers to any native HER2 from any vertebrate species, including mammals such as primates (e.g., humans) non-human primates (e.g., cynomolgus monkeys) and rodents (e.g., mice and rats). The term encompasses “full-length,” unprocessed HER2, as well as any form of HER2 that results from processing in a cell. The term also encompasses naturally occurring variants of HER2, e.g., splice variants or allelic variants. In one aspect, HER2 is human HER2. The amino acid sequence of human HER2 is shown in UniProt entry number Q9UK79 (version 95).

[0118] “Epidermal Growth Factor Receptor (EGFR)” also known as proto-oncogene c-ErbB-1 or receptor tyrosine-protein kinase erbB-1, unless otherwise indicated, refers to any native EGFR from any vertebrate source, including mammals such as primates (e.g., humans), non-human primates (e.g., cynomolgus monkeys) and rodents (e.g., mice and rats). The amino acid sequence of human EGFR is shown in UniProt accession number P00533.

[0119] As used herein, “T cell antigen” refers to any antigen present on the surface of a T lymphocyte.

[0120] The term “PD-1”, also known as CD279, PD1 or Programmed cell Death protein 1, refers to any native PD-1 from any vertebrate source, including mammals such as primates (e.g., humans), non-human primates (e.g., cynomolgus monkeys) and rodents (e.g., mice and rats), in particular the human protein PD-1 having the amino acid sequence shown in UniProt (www.uniprot.org) accession number Q15116.

[0121] The term "interferon gamma" or "IFNγ" or "IFN-γ," as used herein, unless otherwise indicated, refers to any native IFNγ from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses unprocessed IFNγ as well as any form of IFNγ that results from processing in the cell. The term also encompasses naturally occurring variants of IFNγ, e.g., splice variants or allelic variants.

[0122] The term "interferon gamma" or "IFNγ" or "IFN-γ," as used herein, unless otherwise indicated, refers to any native IFNγ from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses unprocessed IFNγ as well as any form of IFNγ that results from processing in the cell. The term also encompasses naturally occurring variants of IFNγ, e.g., splice variants or allelic variants.

[0123] Cytokine receptors are cell surface glycoproteins that specifically bind cytokines and transduce their signals. Typically, cytokine receptors act as oligomeric complexes, usually consisting of two to four receptor chains, also called subunits, which can be identical or different. Thus, the term "cytokine receptor complex" refers to a cytokine receptor composed of at least two subunits.

[0124] The IFNγ receptor complex comprises an IFNγR1 subunit and an IFNγR2 subunit. The term "interferon gamma receptor 1" or "IFNγR1" (also known as CD119 (cluster of differentiation 119) or interferon gamma receptor alpha chain (IFNγRα)), unless otherwise indicated, refers to any native IFNγR1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed IFNγR1 as well as any form of IFNγR1 that results from processing in the cell. The term also encompasses naturally occurring variants of IFNγR1, e.g., splice variants or allelic variants. In certain embodiments, the IFNγR1 is a human IFNγR1.

[0125] The term "interferon gamma receptor 2" or "IFNγR2" (also known as interferon gamma receptor beta chain (IFNγRβ)), unless otherwise indicated, refers to any native IFNγR2 from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and rats). The term encompasses "full-length" unprocessed IFNγR2, as well as any form of IFNγR2 that results from processing in the cell. The term also encompasses naturally occurring variants of IFNγR2, e.g. splice variants or allelic variants. In certain embodiments, the IFNγR2 is a human IFNγR2.

[0126] The term "IL-2Rα" or "α subunit of the IL-2 receptor" (also known as CD25), unless otherwise indicated, refers to any native IL-2Rα from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and rats). The term encompasses "full-length" unprocessed IL-2Rα as well as any form of IL-2Rα that results from processing in the cell. The term also encompasses naturally occurring variants of IL-2Rα, e.g. splice variants or allelic variants. In certain embodiments, the IL-2Rα is a human IL-2Rα.

[0127] The term "IL-2Rβ" or "β subunit of the IL-2 receptor" (also known as CD122 or p70), unless otherwise indicated, refers to any native IL-2Rβ from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and rats). The term encompasses "full-length" unprocessed IL-2Rβ as well as any form of IL-2Rβ that results from processing in the cell. The term also encompasses naturally occurring variants of IL-2Rβ, e.g. splice variants or allelic variants. In certain embodiments, the IL-2Rβ is a human IL-2Rβ.

[0128] The term "IL-2Ry" or "gamma subunit of the IL-2 receptor" (also known as common cytokine receptor gamma subunit, common gamma chain, yc, or CD132), refers to any native IL-2Ry from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses "full-length," unprocessed IL-2Ry as well as any form of IL-2Ry that results from processing in the cell. The term also encompasses naturally occurring variants of IL-2Ry, e.g., splice variants or allelic variants. In certain embodiments, the IL-2Ry is a human IL-2Ry.

[0129] Different associations of the individual IL-2R subunits IL-2Ra, IL-2Rb, and IL-2Ry can result in three forms of IL-2R, which differ in their affinity for IL-2. High affinity IL-2R refers to the heterotrimeric form of IL-2R, composed of IL-2Ra, IL-2Rb, and IL-2Ry. Intermediate affinity IL-2R refers to the heterodimeric form of IL-2R, composed of IL-2Rb and IL-2Ry. And low affinity IL-2R refers to the monomeric form of IL-2R, composed of IL-2Ra only (for review, see, e.g., Olejniczak and Kasprzak, Med Sci Monit 14, RA179-189 (2008)).

[0130] As used herein, the term "IL-2 receptor complex" refers to a high affinity IL-2 receptor or an intermediate affinity IL-2 receptor.

[0131] The term "Fc domain" or "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, an antibody produced by a host cell can be subject to post-translational cleavage of one or more, particularly one or two, amino acids from the heavy chain C-terminus. Thus, an antibody produced by a host cell by expression of a particular nucleic acid molecule encoding a full-length heavy chain can include a full-length heavy chain, or the antibody can include a cleaved variant of the full-length heavy chain. This can be the case where the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, numbered according to the Kabat EU index). Thus, the C-terminal lysine (Lys447) or the C-terminal glycine (Gly446) and lysine (Lys447) of the Fc region can or can not be present. In one aspect, a heavy chain comprising an Fc region (subunit) as specified herein comprised in a binding molecule according to the application comprises the additional C-terminal lysine (K447, numbered according to the Kabat EU index). In one aspect, a heavy chain comprising an Fc region (subunit) as specified herein comprised in a binding molecule according to the application comprises the C-terminal glycine residue (G446, numbered according to the Kabat EU index) and does not comprise the C-terminal lysine (Lys477). Unless otherwise indicated herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system (also called the EU index), as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 (see also above). A "subunit" of an Fc domain as used herein refers to one of the two polypeptides forming a dimeric Fc domain, i.e. a polypeptide comprising the C-terminal constant region of an immunoglobulin heavy chain, which is capable of stable self-association. For example, a subunit of an IgG Fc domain comprises the IgG CH2 and IgG CH3 constant domains.

[0132] A "modification that promotes association of a first subunit and a second subunit of an Fc domain" is a manipulation of the peptide backbone or a post-translational modification of an Fc domain subunit that reduces or prevents a polypeptide comprising an Fc domain subunit from associating with the same polypeptide to form a homodimer. As used herein, a "modification that promotes association" preferably includes separate modifications made to each of the two Fc domain subunits (i.e., a first subunit and a second subunit of an Fc domain) that are desired to associate, wherein the modifications complement each other to promote association of the two Fc domain subunits. For example, a modification that promotes association can alter the structure or charge of one or both of the Fc domain subunits so as to make their association favorable, either sterically or electrostatically, respectively. Thus, (hetero) dimerization occurs between a polypeptide comprising a first Fc domain subunit and a polypeptide comprising a second Fc domain subunit, which can be different with respect to additional components (e.g., antigen binding domains) fused to each subunit. In one aspect, a modification that promotes association of a first subunit and a second subunit of an Fc domain includes an amino acid mutation, in particular an amino acid substitution, in the Fc domain. In a particular aspect, a modification that promotes association of a first subunit and a second subunit of an Fc domain comprises separate amino acid mutations, in particular amino acid substitutions, in each of the two subunits of the Fc domain.

[0133] One method of heterodimerization known in the art is the so-called "knob-into-hole" technology, which is described in detail in several examples in, e.g., WO96 / 027011; Ridgway, J.B., et al., Protein Eng. 9 (1996) 617-621; Merchant, A.M., et al., Nat. Biotechnol. 16 (1998) 677-681; and WO98 / 050431. In the "knob-into-hole" technology, specific amino acids on each of the two CH3 domains in the tertiary structure of an antibody are engineered to create a protuberance ("knob") in one CH3 domain and a cavity ("hole") in the other CH3 domain, respectively, within the interface formed between the two CH3 domains. In the tertiary structure of a multispecific antibody, the protuberance introduced into one CH3 domain can be positioned within the cavity introduced into the other CH3 domain.

[0134] The term "effector functions" refers to those biological activities of an antibody that are attributable to its Fc region, and which vary with the isotype of the antibody. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), cytokine secretion, immune complex-mediated antigen uptake by antigen presenting cells, down regulation of cell surface receptors (e.g., B-cell receptor), and B-cell activation.

[0135] An "activating Fc receptor" is an Fc receptor that, upon engagement by the Fc domain of an antibody, initiates signaling events that stimulate the cell bearing the receptor to perform an effector function. Human activating Fc receptors include FcyRIIIa (CD16a), FcyRI (CD64), FcyRIIa (CD32), and FcaRI (CD89).

[0136] Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune mechanism that results in the lysis of antibody-coated target cells by immune effector cells. The target cell is a cell that specifically binds to an antibody or derivative thereof comprising an Fc region, typically through a protein portion of the N-terminus of the Fc region. As used herein, the term "reduced ADCC" is defined as a decrease in the number of target cells lysed by the ADCC mechanism defined above in a given time and at a given concentration of antibody in the medium surrounding the target cells, and / or an increase in the concentration of antibody necessary to achieve lysis of a given number of target cells by the ADCC mechanism in a given time in the medium surrounding the target cells. The reduction in ADCC is relative to the ADCC mediated by the same antibody produced using the same standard production, purification, formulation, and storage methods known to those skilled in the art, but which has not been engineered. For example, a reduction in ADCC mediated by an antibody comprising an amino acid substitution in the Fc domain that reduces ADCC is relative to the ADCC mediated by the same antibody without that amino acid substitution in the Fc domain. Suitable assays for measuring ADCC are well known in the art (see, e.g., PCT Publication No. WO 2006 / 082515 or PCT Publication No. WO 2012 / 130831).

[0137] "Reduced binding" (e.g., reduced binding to an Fc receptor) means a decrease in the affinity for the corresponding interaction, as measured, e.g., by SPR. For the sake of clarity, this term also includes reducing the affinity to zero (or below the detection limit of the analytical method), i.e., completely abolishing the interaction. Conversely, "increased binding" means an increase in the binding affinity for the corresponding interaction.

[0138] “Affinity” refers to the strength of the sum total of noncovalent interactions between individual binding sites of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, “binding affinity” as used herein refers to intrinsic binding affinity, which reflects 1:1 interactions between members of a binding pair, e.g., an antibody and an antigen. The affinity of a molecule X for its partner Y can be generally represented by the dissociation constant (KD). Affinity can be measured by well-established methods known in the art, including those described herein. The preferred method for measuring affinity is surface plasmon resonance (SPR).

[0139] As used herein, the term “engineered, engineered, engineered” is considered to include any manipulation of the peptide backbone, or post-translational modification of a naturally occurring or recombinant polypeptide or fragment thereof. Engineering includes modifications to the amino acid sequence, glycosylation pattern, or side chain groups of individual amino acids, and combinations of these methods.

[0140] The term “amino acid mutation” as used herein is meant to encompass amino acid substitutions, deletions, insertions, and modifications. Any combination of substitutions, deletions, insertions and modifications can be made to arrive at a final construct, provided that the final construct has the desired characteristics, e.g., reduced binding to an Fc receptor, or increased association with another peptide. Amino acid sequence deletions and insertions include amino- and / or carboxyl-terminal deletions and insertions. A preferred amino acid mutation is an amino acid substitution. For the purpose of altering, e.g., the binding characteristics of an Fc region, non-conservative amino acid substitutions, i.e., the substitution of one amino acid for another amino acid with different structural and / or chemical properties, are particularly preferred. Amino acid substitutions include replacement of a non-naturally occurring amino acid or a naturally occurring amino acid derivative of the twenty standard amino acids (e.g., 4-hydroxyproline, 3-methylhistidine, ornithine, homoserine, 5-hydroxylysine). Genetic or chemical methods well known in the art can be used to produce amino acid mutations. Genetic methods can include site-directed mutagenesis, PCR, gene synthesis, and the like. Methods of altering amino acid side chain groups by means other than genetic engineering, such as chemical modification, are also contemplated to be useful. Various designations can be used herein to indicate the same amino acid mutation. For example, substitution of proline at position 329 of an Fc domain to glycine can be denoted as 329G, G329, G329, P329G, or Pro329Gly.

[0141] By "fusion" is meant that components (e.g., Fab molecules and Fc domain subunits) are linked by peptide bonds, either directly or via one or more peptide linkers. The term "fusion point" refers to the point on one component where the component is fused to another component. For example, a cytokine receptor binding domain can be fused at its C-terminus to the N-terminus of a VH domain of a target binding domain. Thus, the fusion point on the cytokine receptor binding domain is the C-terminus, and the fusion point on the target binding domain is the N-terminus.

[0142] "Percentage (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the candidate sequence with the reference polypeptide sequence, introducing gaps if necessary to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or the FASTA program package. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Alternatively, the percent identity values can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code has been filed with the U.S. Copyright Office, Washington D.C., 20559-200, where it is registered under U.S. Copyright Registration No. TXU510087, and is described in WO 2001 / 007611.

[0143] Unless otherwise indicated, for purposes herein, amino acid sequence identity % values are generated using the FASTA package version 36.3.8c or higher, using the ggsearch program with the BLOSUM50 comparison matrix. The FASTA program package was authored by W. R. Pearson and D. J. Lipman (“Improved Tools for Biological Sequence Analysis”, PNAS 85 (1988) 2444-2448), W. R. Pearson (“Effective protein sequence comparison” Meth. Enzymol. 266 (1996) 227-25 258), and Pearson et al. (Genomics 46 (1997) 24-36), and is publicly available from www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta.

[0144] Alternatively, sequences can be compared using the public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi, using the ggsearch (global protein:protein) program and default options (BLOSUM50; open:-10; ext:-2; Ktup = 2) to ensure that a global rather than local alignment is performed. The percent amino acid identity is given in the output alignment header.

[0145] Cytokine mimetic

[0146] The present inventors have found that antigen binding domain pairs capable of binding different cytokine receptor subunits of a cytokine receptor complex (hereinafter referred to as cytokine receptor binding domains) can act as cytokine agonists, i.e. mimic naturally occurring cytokines. Cytokine agonists are also referred to as cytokine mimics. This is demonstrated by combining the cytokine receptor binding domain pairs capable of binding different cytokine receptor subunits in a single antigen binding molecule. The antibody format of these molecules can provide advantageous properties compared to natural or recombinant cytokines. To achieve conditional activation of the cytokine receptor, the cytokine receptor binding domain pairs are split into two different antigen binding molecules, i.e. split molecules or split antibodies. These antigen binding molecules further comprise an antigen binding domain capable of binding a target antigen, hereinafter referred to as target binding domain. By target dependent assembly of the cytokine receptor binding domain pairs, these molecules can act as cytokine mimics. The use of a target dependent approach further allows to direct the agonistic activity to a site of interest, such as a cell or tissue expressing the target. The target binding domains of the molecules are capable of binding the same target antigen simultaneously, i.e. they bind different epitopes of said antigen and are non-competitive. Such pairs of target binding domains are also referred to as biparatopic target binding domains. Assembly of the cytokine receptor binding domains by biparatopic target binding domains allows to specifically target the cytokine receptor binding domains to a site of interest, i.e. a cell or environment where the target antigen is expressed, to act as cytokine mimics. Thus, split antigen binding molecule pairs are biparatopic pairs of antigen binding molecules.

[0147] Split bi-paratopic antigen binding molecule pairs

[0148] In one aspect, the present application provides a pair of antigen binding molecules specifically binding to a target antigen, the pair of antigen binding molecules comprising: a) a first antigen binding molecule comprising i) a first target binding domain, ii) a first cytokine receptor binding domain, and iii) a Fc domain; and a second antigen binding molecule comprising i) a second target binding domain, ii) a second cytokine receptor binding domain, and iii) a Fc domain; wherein the first target binding domain is capable of binding a first epitope of the target antigen and the second target binding domain is capable of binding a second epitope of the target antigen, wherein the first target binding domain and the second target binding domain do not compete for binding on the target antigen; and wherein the first cytokine receptor binding domain is capable of binding a first cytokine receptor subunit and the second cytokine receptor binding domain is capable of binding a second cytokine receptor subunit.

[0149] The pairs of antigen binding molecules described above and herein can individually or in combination bind any of the features described below (unless context dictates otherwise).

[0150] Cytokine receptor binding domain

[0151] According to the application, each antigen binding molecule of the pair of antigen binding molecules comprises a cytokine receptor binding domain. The first antigen binding molecule comprises a first cytokine receptor binding domain and the second antigen binding molecule comprises a second cytokine receptor binding domain. The cytokine receptor binding domains comprised in the pair of antigen binding molecules bind to different cytokine receptor subunits. Each cytokine receptor binding domain of the pair of antigen binding molecules binds to a different cytokine receptor subunit of the cytokine receptor complex. Thus, the first antigen binding molecule comprises a first cytokine receptor binding domain capable of binding to a first cytokine receptor subunit and the second antigen binding molecule comprises a second cytokine receptor binding domain capable of binding to a second cytokine receptor subunit. The first cytokine receptor subunit and the second cytokine receptor subunit are subunits of the cytokine receptor complex.

[0152] The cytokine receptor complex can be an IFNy receptor complex, an IL-2 receptor complex, an IL-7 receptor complex, an IL-12 receptor complex, or an IL-18 receptor complex. Thus, the first cytokine receptor binding domain and the second cytokine receptor binding domain can bind to different subunits of an IFNy receptor complex, an IL-2 receptor complex, an IL-7 receptor complex, an IL-12 receptor complex, or an IL-18 receptor complex. In one embodiment, the first cytokine receptor binding domain and the second cytokine receptor binding domain bind to subunits of an IFNy receptor complex. Thus, in one embodiment, the first cytokine receptor binding domain is capable of binding to IFNyRl and the second cytokine receptor binding domain is capable of binding to IFNyR2. Alternatively, the first cytokine receptor binding domain is capable of binding to IFNyR2 and the second cytokine receptor binding domain is capable of binding to IFNyRl. In a further embodiment, the first cytokine receptor binding domain and the second cytokine receptor binding domain bind to subunits of an IL-2 receptor complex. Thus, in one embodiment, the first cytokine receptor binding domain is capable of binding to IL-2Rβ and the second cytokine receptor binding domain is capable of binding to IL-2Rγ. In one embodiment, the first cytokine receptor binding domain is capable of binding to IL-2Rγ and the second cytokine receptor binding domain is capable of binding to IL-2Rβ. In another embodiment, the first cytokine receptor binding domain and the second cytokine receptor binding domain bind to subunits of an IL-7 receptor complex. Thus, in one embodiment, the first cytokine receptor binding domain is capable of binding to IL-7Rα and the second cytokine receptor binding domain is capable of binding to IL-2Rγ. In one embodiment, the first cytokine receptor binding domain is capable of binding to IL-2Rγ and the second cytokine receptor binding domain is capable of binding to IL-7Rα. In a further embodiment, the first cytokine receptor binding domain and the second cytokine receptor binding domain bind to subunits of an IL-12 receptor complex. Thus, in one embodiment, the first cytokine receptor binding domain is capable of binding to IL-12Rβl and the second cytokine receptor binding domain is capable of binding to IL-12Rβ2. In one embodiment, the first cytokine receptor binding domain is capable of binding to IL-12Rβ2 and the second cytokine receptor binding domain is capable of binding to IL-12Rβl.

[0153] The first and / or second cytokine receptor binding domain can be an antibody fragment, such as Fv, Fab, scFv, scFab, or a single domain antibody. In one embodiment, the first and / or second cytokine receptor binding domain is a single domain antibody. In particular embodiments, the first and second cytokine receptor binding domain is a VHH domain.

[0154] In one aspect, the first cytokine receptor binding domain comprises an amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the second cytokine receptor binding domain comprises an amino acid sequence selected from SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10. In one aspect, the first cytokine receptor binding domain comprises an amino acid sequence selected from SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, and the second cytokine receptor binding domain comprises an amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5. In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 3, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 7. In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 7, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 3.

[0155] In one aspect, the first cytokine receptor binding domain comprises an amino acid sequence selected from SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, and the second cytokine receptor binding domain comprises an amino acid sequence selected from SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65. In one aspect, the first cytokine receptor binding domain comprises an amino acid sequence selected from SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, and the second cytokine receptor binding domain comprises an amino acid sequence selected from SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60. In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 60, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62. In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 60.

[0156] In one aspect, the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65. In one aspect, the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192. In one aspect, the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62.In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192. In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 182, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62. In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 182. In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 186, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62. In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 186. In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 190, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62. In one aspect, the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 190.

[0157] Target antigen binding domain

[0158] According to the application, each antigen binding molecule of the pair of antigen binding molecules comprises a target binding domain. The first antigen binding molecule comprises a first target binding domain and the second antigen binding molecule comprises a second target binding domain. The first target binding domain and the second target binding domain bind to the same target, i.e. the same antigen. However, the first target binding domain and the second target binding domain bind to different epitopes of said target. The first target binding domain is capable of binding to a first epitope on the target antigen and the second target binding domain is capable of binding to a second epitope on the target antigen. The first target binding domain and the second target binding domain are capable of binding to the target simultaneously, i.e. the target binding domains are non-competitive domains. The first target binding domain does not compete with the second target binding domain for binding to the target antigen.

[0159] The target binding domain of the first antigen binding molecule and / or the second antigen binding molecule can be an antibody fragment. In one embodiment, the first target binding domain is an antibody fragment and the second target binding domain is an antibody fragment. In one embodiment, the first antigen binding molecule comprises a first target binding domain, wherein the target binding domain is an antibody fragment, and the second antigen binding molecule comprises a second target binding domain, wherein the target binding domain is an antibody fragment. The target binding domain of the first antigen binding molecule and / or the second antigen binding molecule can be a Fv, a Fab, a scFv, a scFab molecule or a single domain antibody. In one embodiment, the first antigen binding molecule comprises a first target binding domain, wherein the target binding domain is a Fv, a Fab, a scFv, a scFab molecule or a single domain antibody, and the second antigen binding molecule comprises a second target binding domain, wherein the target binding domain is a Fv, a Fab, a scFv, a scFab molecule or a single domain antibody.

[0160] In one embodiment, the target binding domain of the first antigen binding molecule and / or the second antigen binding molecule is a Fab molecule. In one embodiment, the first target binding domain is a Fab molecule and the second target binding domain is a Fab molecule. In one embodiment, the first antigen binding molecule comprises a first target binding domain, wherein the target binding domain is a Fab molecule, and the second antigen binding molecule comprises a second target binding domain, wherein the target binding domain is a Fab molecule. In one embodiment, the first target binding domain comprises a heavy chain variable domain (VH1), a light chain variable domain (VL1), a heavy chain constant domain (CH11) and a light chain constant domain (CL1). In one embodiment, the second target binding domain comprises a heavy chain variable domain (VH2), a light chain variable domain (VL2), a heavy chain constant domain (CH12) and a light chain constant domain (CL2).

[0161] The target binding domain can be a cross-Fab. In one embodiment, the first target binding domain is a cross-Fab. In another embodiment, the second target binding domain is a cross-Fab. In one embodiment, the first antigen binding molecule comprises a first target binding domain, wherein the target binding domain is a Fab molecule, wherein the Fab molecule is a cross-Fab, and the second antigen binding molecule comprises a second target binding domain, wherein the target binding domain is a Fab molecule, wherein the Fab molecule is not a cross-Fab, i.e. a regular Fab molecule. In one embodiment, the first antigen binding molecule comprises a first target binding domain, wherein the target binding domain is a Fab molecule, wherein the Fab molecule is a regular Fab molecule, and the second antigen binding molecule comprises a second target binding domain, wherein the target binding domain is a Fab molecule, wherein the Fab molecule is a cross-Fab.

[0162] The first target binding domain and the second target binding domain both specifically bind to the same target antigen. The target antigen can be a tumor associated antigen or a T cell antigen.

[0163] The target antigen can be a tumor associated antigen, such as CEA, FAP, Her2, Her3 or EGFR. The target antigen can be a human tumor associated antigen. Thus, the target antigen can be human CEA, human FAP, human Her2, human Her3 or human EGFR. Thus, in one aspect, the first target binding domain is capable of binding to a first epitope of CEA and the second target binding domain is capable of binding to a second epitope of CEA. In one aspect, the first target binding domain is capable of binding to a first epitope of FAP and the second target binding domain is capable of binding to a second epitope of FAP. In one aspect, the first target binding domain is capable of binding to a first epitope of Her2 and the second target binding domain is capable of binding to a second epitope of Her2. In one aspect, the first target binding domain is capable of binding to a first epitope of Her3 and the second target binding domain is capable of binding to a second epitope of Her3. In one aspect, the first target binding domain is capable of binding to a first epitope of EGFR and the second target binding domain is capable of binding to a second epitope of EGFR.

[0164] In one aspect, the first target binding domain comprises a VH1 of SEQ ID NO: 20 and a VL1 of SEQ ID NO: 21 and the second target binding domain comprises a VH2 of SEQ ID NO: 22 and a VL2 of SEQ ID NO: 23. In one aspect, the first target binding domain comprises a VH1 of SEQ ID NO: 22 and a VL1 of SEQ ID NO: 23 and the second target binding domain comprises a VH2 of SEQ ID NO: 20 and a VL2 of SEQ ID NO: 21. In one aspect, the first target binding domain comprises a VH1 of SEQ ID NO: 114 and a VL1 of SEQ ID NO: 115 and the second target binding domain comprises a VH2 of SEQ ID NO: 116 and a VL2 of SEQ ID NO: 117. In one aspect, the first target binding domain comprises a VH1 of SEQ ID NO: 116 and a VL1 of SEQ ID NO: 117 and the second target binding domain comprises a VH2 of SEQ ID NO: 114 and a VL2 of SEQ ID NO: 115. In one aspect, the first target binding domain comprises a VH1 of SEQ ID NO: 130 and a VL1 of SEQ ID NO: 131 and the second target binding domain comprises a VH2 of SEQ ID NO: 132 and a VL2 of SEQ ID NO: 133. In one aspect, the first target binding domain comprises a VH1 of SEQ ID NO: 132 and a VL1 of SEQ ID NO: 133 and the second target binding domain comprises a VH2 of SEQ ID NO: 130 and a VL2 of SEQ ID NO: 131. In one aspect, the first target binding domain comprises a VH1 of SEQ ID NO: 140 and a VL1 of SEQ ID NO: 141 and the second target binding domain comprises a VH2 of SEQ ID NO: 142 and a VL2 of SEQ ID NO: 143. In one aspect, the first target binding domain comprises a VH1 of SEQ ID NO: 142 and a VL1 of SEQ ID NO: 143 and the second target binding domain comprises a VH2 of SEQ ID NO: 140 and a VL2 of SEQ ID NO: 141.

[0165] The target antigen can be a T cell antigen, such as PD-1 or LAG-3. The target antigen can be human PD-1 or human LAG-3. Thus, in one aspect, the first target binding domain is capable of binding a first epitope of PD-1 and the second target binding domain is capable of binding a second epitope of PD-1. In one aspect, the first target binding domain is capable of binding a first epitope of LAG-3 and the second target binding domain is capable of binding a second epitope of LAG-3. In one aspect, the first target binding domain comprises VH1 of SEQ ID NO: 76 and VL1 of SEQ ID NO: 77 and the second target binding domain comprises VH2 of SEQ ID NO: 78 and VL2 of SEQ ID NO: 79. In one aspect, the first target binding domain comprises VH1 of SEQ ID NO: 78 and VL1 of SEQ ID NO: 79 and the second target binding domain comprises VH2 of SEQ ID NO: 76 and VL2 of SEQ ID NO: 77. In one aspect, the first target binding domain comprises VH1 of SEQ ID NO: 93 and VL1 of SEQ ID NO: 94 and the second target binding domain comprises VH2 of SEQ ID NO: 78 and VL2 of SEQ ID NO: 79. In one aspect, the first target binding domain comprises VH1 of SEQ ID NO: 78 and VL1 of SEQ ID NO: 79 and the second target binding domain comprises VH2 of SEQ ID NO: 93 and VL2 of SEQ ID NO: 94. In one aspect, the first target binding domain comprises VH1 of SEQ ID NO: 150 and VL1 of SEQ ID NO: 151 and the second target binding domain comprises VH2 of SEQ ID NO: 152 and VL2 of SEQ ID NO: 153. In one aspect, the first target binding domain comprises VH1 of SEQ ID NO: 152 and VL1 of SEQ ID NO: 153 and the second target binding domain comprises VH2 of SEQ ID NO: 150 and VL2 of SEQ ID NO: 151.

[0166] Fc domain

[0167] According to the application, the first antigen binding molecule and the second antigen binding molecule comprise an Fc domain.

[0168] The Fc domain of a binding molecule consists of a pair of polypeptide chains, a first Fc domain subunit and a second Fc domain subunit. The first Fc domain subunit and the second Fc domain subunit can comprise heavy chain domains of an immunoglobulin molecule. For example, the Fc domain of an immunoglobulin G (IgG) molecule is a dimer, each subunit of which comprises CH2 and CH3 IgG heavy chain constant domains. The two subunits of an Fc domain are capable of stable association with one another.

[0169] In one aspect, the first antigen binding molecule comprises an Fc domain consisting of a first Fc domain subunit and a second Fc domain subunit, and / or the second antigen binding molecule comprises an Fc domain consisting of a first Fc domain subunit and a second Fc domain subunit. In one aspect, the first antigen binding molecule comprises an Fc domain consisting of a first Fc domain subunit and a second Fc domain subunit, and the second antigen binding molecule comprises an Fc domain consisting of a first Fc domain subunit and a second Fc domain subunit. In one aspect, each of the antigen binding molecules comprises no more than one Fc domain.

[0170] In one aspect, the Fc domain of the first antigen binding molecule and / or the second antigen binding molecule can be an IgG Fc domain. In a particular embodiment, the Fc domain is an IgGl Fc domain. In another particular embodiment, the Fc domain is an IgG4 Fc domain.

[0171] In a more particular aspect, the Fc domain is an IgG4 Fc domain comprising an amino acid substitution at position S228 (Kabat EU index numbering), in particular the amino acid substitution S228P. This amino acid substitution reduces Fab arm exchange of IgG4 antibodies in vivo (see Stubenrauch et al., Drug Metabolism and Disposition 38, 84-91 (2010)). In a further aspect, the Fc domain is a human Fc domain. In a particular aspect, the Fc domain is an IgGl Fc domain.

[0172] In one aspect, the Fc domain comprises a modification that promotes association of the first subunit and the second subunit of the Fc domain. Fc domain modifications that promote heterodimerization are further described below.

[0173] In one aspect, the Fc domain comprises one or more amino acid substitution that reduces binding to an Fc receptor and / or effector function. Fc domain modifications that reduce Fc receptor binding and / or reduce effector function are further described below.

[0174] Fc domain modifications that promote heterodimerization

[0175] The antigen binding molecules according to the application comprise a target binding domain and a cytokine receptor binding domain, which can be fused to a first Fc domain subunit and / or a second Fc domain subunit, whereby the two Fc domain subunits are usually comprised in two different polypeptide chains. Recombinant co-expression of these polypeptides and subsequent dimerization leads to several possible combinations of the two polypeptides. In order to improve the yield and purity of the antigen binding molecules in recombinant production, it would therefore be advantageous to introduce modifications in the Fc domain of the antigen binding molecules that promote association of the desired polypeptides.

[0176] Thus, in a particular aspect, the Fc domain of the antigen binding molecules according to the application comprises a modification that promotes association of the first subunit with the second subunit of the Fc domain. The most widespread interprotein interaction site between the two subunits of a human IgG Fc domain is in the CH3 domain of the Fc domain. Thus, in one aspect, the modification is in the CH3 domain of the Fc domain.

[0177] There are several methods to modify the CH3 domain of the Fc domain to enforce heterodimerization, which are described in detail, for example, in WO 96 / 27011, WO 98 / 050431, EP 1870459, WO 2007 / 110205, WO 2007 / 147901, WO 2009 / 089004, WO 2010 / 129304, WO 2011 / 90754, WO 2011 / 143545, WO 2012058768, WO 2013157954, WO 2013096291. Generally, in all such methods, the CH3 domain of the first subunit of the Fc domain and the CH3 domain of the second subunit of the Fc domain are engineered in a complementary fashion, such that each CH3 domain (or the heavy chain comprising it) can no longer homodimerize with itself, but is forced to heterodimerize with the other CH3 domain that is complementarily engineered (such that the first and second CH3 domains heterodimerize and no homodimers are formed between two first or two second CH3 domains).

[0178] In a specific aspect, the modification that promotes association of the first and second subunit of the Fc domain is a so-called "knob-into-hole" modification, which comprises a "knob" modification in one of the two subunits of the Fc domain and a "hole" modification in the other of the two subunits of the Fc domain.

[0179] Knob-into-hole technology is described, e.g., in US 5,731,168; US 7,695,936; Ridgway et al., Prot Eng 9, 617-621 (1996); and Carter, J Immunol Meth 248, 7-15 (2001). Generally, the method involves introducing a protuberance ("knob") at the interface of a first polypeptide and a corresponding cavity ("hole") in the interface of a second polypeptide, such that the protuberance can be positioned in the cavity in order to promote formation of a heterodimer and impede formation of a homodimer. The protuberance is constructed by substituting a small amino acid side chain from the interface of the first polypeptide with a larger side chain, e.g., tyrosine or tryptophan.

[0180] A compensating cavity of the same or similar size as the protuberance is created in the interface of the second polypeptide by substituting a large amino acid side chain with a smaller amino acid side chain, e.g., alanine or threonine.

[0181] Thus, in a preferred aspect, in the CH3 domain of the first subunit of the Fc domain of the antigen binding molecule, an amino acid residue is substituted with an amino acid residue having a larger side chain volume, thereby creating a protuberance within the CH3 domain of the first subunit, which is positionable in a cavity within the CH3 domain of the second subunit, and in the CH3 domain of the second subunit of the Fc domain, an amino acid residue is substituted with an amino acid residue having a smaller side chain volume, thereby creating a cavity within the CH3 domain of the second subunit, which is positionable in the protuberance within the CH3 domain of the first subunit.

[0182] Preferably, the amino acid residue having a larger side chain volume is selected from the group consisting of arginine (R), phenylalanine (F), tyrosine (Y), and tryptophan (W). Preferably, the amino acid residue having a smaller side chain volume is selected from the group consisting of alanine (A), serine (S), threonine (T), and valine (V). The protuberance and the cavity can be prepared by altering the nucleic acid encoding the polypeptide, e.g., by site-specific mutagenesis or by peptide synthesis.

[0183] In a particular aspect, in the CH3 domain of the first subunit of the Fc domain ("knob" subunit), the threonine residue at position 366 is replaced by a tryptophan residue (T366W), and in the CH3 domain of the second subunit of the Fc domain ("hole" subunit), the tyrosine residue at position 407 is replaced by a valine residue (Y407V). In one aspect, in the second subunit of the Fc domain, additionally the threonine residue at position 366 is replaced by a serine residue (T366S), and the leucine residue at position 368 is replaced by an alanine residue (L368A) (numbering according to the EU index of Kabat).

[0184] In a yet further aspect, in the first subunit of the Fc domain, additionally, the serine residue at position 354 is replaced by a cysteine residue (S354C) or the glutamic acid residue at position 356 is replaced by a cysteine residue (E356C) (in particular, the serine residue at position 354 is replaced by a cysteine residue), and in the second subunit of the Fc domain, additionally, the tyrosine residue at position 349 is replaced by a cysteine residue (Y349C) (numbering according to the EU index of Kabat). Introduction of these two cysteine residues leads to the formation of a disulfide bridge between the two subunits of the Fc domain, thereby further stabilizing the dimer (Carter, J Immunol Methods 248, 7-15 (2001)).

[0185] In a particular aspect, the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W, and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, L368A and Y407V (numbering according to the EU index of Kabat).

[0186] Other CH3 modification techniques for effecting heterodimerization are envisaged as alternatives according to the application and are described, for example, in WO 96 / 27011, WO 98 / 050431, EP 1870459, WO 2007 / 110205, WO 2007 / 147901, WO 2009 / 089004, WO 2010 / 129304, WO 2011 / 90754, WO 2011 / 143545, WO 2012 / 058768, WO 2013 / 157954, WO 2013 / 096291.

[0187] In one aspect, the heterodimerization approach described in EP 1870459 is used alternatively. This approach is based on the introduction of charged amino acids with opposite charges at specific amino acid positions in the CH3 / CH3 domain interface between the two subunits of the Fc domain.

[0188] A particular aspect of the antigen binding molecules of the application is the amino acid mutation R409D; K370E in one of the two CH3 domains (of the Fc domain), and the amino acid mutation D399K; E357K in the other CH3 domain of the Fc domain (numbering according to the Kabat EU index).

[0189] In one aspect, the antigen binding molecules of the application comprise the amino acid mutation T366W in the CH3 domain of the first subunit of the Fc domain and the amino acid mutations T366S, L368A, Y407V in the CH3 domain of the second subunit of the Fc domain, and additionally the amino acid mutation R409D; K370E in the CH3 domain of the first subunit of the Fc domain, and the amino acid mutation D399K; E357K in the CH3 domain of the second subunit of the Fc domain (numbering according to the Kabat EU index).

[0190] In one aspect, the antigen binding molecules of the application comprise the amino acid mutation S354C, T366W in the CH3 domain of the first subunit of the Fc domain and the amino acid mutations Y349C, T366S, L368A, Y407V in the CH3 domain of the second subunit of the Fc domain, or the antigen binding molecules comprise the amino acid mutation Y349C, T366W in the CH3 domain of the first subunit of the Fc domain and the amino acid mutations S354C, T366S, L368A, Y407V in the CH3 domain of the second subunit of the Fc domain, and additionally the amino acid mutation R409D; K370E in the CH3 domain of the first subunit of the Fc domain, and the amino acid mutation D399K; E357K in the CH3 domain of the second subunit of the Fc domain (all numbering according to the EU index of Kabat).

[0191] In one aspect, the heterodimerization approach described in WO 2013 / 157953 is used alternatively. In one aspect, the first CH3 domain comprises the amino acid mutation T366K and the second CH3 domain comprises the amino acid mutation L351D (numbering according to Kabat EU index). In a further aspect, the first CH3 domain comprises the additional amino acid mutation L351K. In a further aspect, the second CH3 domain further comprises an amino acid mutation selected from the group consisting of Y349E, Y349D and L368E, in particular L368E (numbering according to Kabat EU index).

[0192] In one aspect, the heterodimerization approach described in WO 2012 / 058768 is used alternatively. In one aspect, the first CH3 domain comprises the amino acid mutations L351Y, Y407A and the second CH3 domain comprises the amino acid mutations T366A, K409F. In a further aspect, the second CH3 domain comprises a further amino acid mutation at position T411, D399, S400, F405, N390 or K392, for example selected from the group consisting of a) T411N, T411R, T411Q, T411K, T411D, T411E or T411W, b) D399R, D399W, D399Y or D399K, c) S400E, S400D, S400R or S400K, d) F405I, F405M, F405T, F405S, F405V or F405W, e) N390R, N390K or N390D, f) K392V, K392M, K392R, K392L, K392F or K392E (numbering according to Kabat EU index). In a further aspect, the first CH3 domain comprises the amino acid mutations L351Y, Y407A and the second CH3 domain comprises the amino acid mutations T366V, K409F. In a further aspect, the first CH3 domain comprises the amino acid mutation Y407A and the second CH3 domain comprises the amino acid mutations T366A, K409F. In a further aspect, the second CH3 domain further comprises the amino acid mutations K392E, T411E, D399R and S400R (numbering according to Kabat EU index).

[0193] In one aspect, the heterodimerization approach described in WO 2011 / 143545 is used alternatively, for example amino acid modifications at positions selected from the group consisting of 368 and 409 (numbering according to Kabat EU index).

[0194] In one aspect, the heterodimerization approach described in WO 2011 / 090762 is used instead, which also uses the knob-in-hole technology described above. In one aspect, the first CH3 domain comprises the amino acid mutation T366W and the second CH3 domain comprises the amino acid mutation Y407A. In one aspect, the first CH3 domain comprises the amino acid mutation T366Y and the second CH3 domain comprises the amino acid mutation Y407T (numbering according to Kabat EU index).

[0195] In one aspect, the antigen binding molecule or Fc domain thereof is of the IgG2 subclass and the heterodimerization approach described in WO 2010 / 129304 is used instead.

[0196] In an alternative aspect, the modification that promotes association of the first and second subunits of the Fc domain comprises a modification that mediates an electrostatic steering effect, such as described in PCT Publication WO 2009 / 089004. Generally, this approach involves replacing one or more amino acid residues at the interface of the two Fc domain subunits with charged amino acid residues, such that homodimer formation becomes electrostatically disfavored, but heterodimerization is electrostatically favored. In some such aspects, the first CH3 domain comprises an amino acid substitution to K392 or N392 with a negatively charged amino acid (e.g., glutamic acid (E) or aspartic acid (D), particularly K392D or N392D), and the second CH3 domain comprises an amino acid substitution to D399, E356, D356, or E357 with a positively charged amino acid (e.g., lysine (K) or arginine (R), particularly D399K, E356K, D356K, or E357K, more particularly D399K and E356K). In further aspects, the first CH3 domain further comprises an amino acid substitution to K409 or R409 with a negatively charged amino acid (e.g., glutamic acid (E) or aspartic acid (D), particularly K409D or R409D). In further aspects, the first CH3 domain further or alternatively comprises an amino acid substitution to K439 and / or K370 with a negatively charged amino acid (e.g., glutamic acid (E) or aspartic acid (D)) (all numbering according to Kabat EU index).

[0197] In one aspect, the heterodimerization approach described in WO 2007 / 147901 is used alternatively. In one aspect, the first CH3 domain comprises the amino acid mutations K253E, D282K and K322D, and the second CH3 domain comprises the amino acid mutations D239K, E240K and K292D (numbering according to Kabat EU index). In one aspect, the heterodimerization approach described in WO 2007 / 110205 is used alternatively.

[0198] In one aspect, the first subunit of the Fc domain comprises the amino acid substitutions K392D and K409D, and the second subunit of the Fc domain comprises the amino acid substitutions D356K and D399K (numbering according to Kabat EU index).

[0199] Fc domain modifications that reduce Fc receptor binding and / or effector function

[0200] The Fc domain confers advantageous pharmacokinetic properties to the antigen binding molecule, including a long serum half-life that facilitates good accumulation in the target tissue and a favorable tissue-blood partitioning ratio. At the same time, however, it can lead to undesired targeting of the binding molecule to Fc receptor-expressing cells, rather than the preferred antigen-bearing cells. Furthermore, co-activation of the Fc receptor signaling pathway can lead to cytokine release, which can result in over-activation of cytokine receptors and severe side effects upon systemic administration. Activation of immune cells other than T cells (bearing Fc receptors) can even decrease the efficacy of the antigen binding molecule pair due to potential destruction of T cells, e.g. by NK cells.

[0201] Accordingly, in particular aspects, the Fc domain of an antigen binding molecule according to the application exhibits reduced binding affinity to an Fc receptor and / or reduced effector function compared to a native IgGl Fc domain. In some such aspects, the Fc domain (or antigen binding molecule comprising the Fc domain) exhibits less than 50%, specifically less than 20%, more specifically less than 10%, and most specifically less than 5% binding affinity compared to a native IgGl Fc domain (or antigen binding molecule comprising a native IgGl Fc domain), and / or less than 50%, specifically less than 20%, more specifically less than 10%, and most specifically less than 5% effector function compared to a native IgGl Fc domain (or antigen binding molecule comprising a native IgGl Fc domain). In one aspect, the Fc domain (or antigen binding molecule comprising the Fc domain) does not substantially bind to an Fc receptor and / or induce effector function. In particular aspects, the Fc receptor is an Fc gamma receptor. In one aspect, the Fc receptor is a human Fc receptor. In one aspect, the Fc receptor is an activating Fc receptor. In specific aspects, the Fc receptor is an activating human Fc gamma receptor, more specifically human Fc gamma RIIIa, Fc gamma RI, or Fc gamma RIIa, most specifically human Fc gamma RIIIa. In one aspect, the effector function is one or more effector functions selected from the group of CDC, ADCC, ADCP, and cytokine secretion. In particular aspects, the effector function is ADCC. In one aspect, the Fc domain exhibits substantially similar binding affinity to neonatal Fc receptor (FcRn) compared to a native IgGl Fc domain. Substantially similar binding to FcRn is achieved when the Fc domain (or antigen binding molecule comprising the Fc domain) exhibits greater than about 70%, specifically greater than about 80%, more specifically greater than about 90% binding affinity to FcRn compared to a native IgGl Fc domain (or antigen binding molecule comprising a native IgGl Fc domain).

[0202] In certain aspects, the Fc domain is engineered to have reduced binding affinity to an Fc receptor and / or reduced effector function as compared to a non-engineered Fc domain. In particular aspects, the Fc domain of the antigen binding molecule comprises one or more amino acid mutations that reduce the binding affinity of the Fc domain to an Fc receptor and / or effector function. Typically, the same one or more amino acid mutations are present in each of the two subunits of the Fc domain. In one aspect, the amino acid mutation(s) reduce the binding affinity of the Fc domain to an Fc receptor. In one aspect, the amino acid mutation(s) reduce the binding affinity of the Fc domain to an Fc receptor by at least 2-fold, at least 5-fold, or at least 10-fold. In aspects where there is more than one amino acid mutation that reduces the binding affinity of the Fc domain to an Fc receptor, the combination of these amino acid mutations can reduce the binding affinity of the Fc domain to an Fc receptor by at least 10-fold, at least 20-fold, or even at least 50-fold. In one aspect, the antigen binding molecule comprising the engineered Fc domain exhibits less than 20%, particularly less than 10%, more particularly less than 5% of the binding affinity to an Fc receptor as compared to an antigen binding molecule comprising a non-engineered Fc domain. In particular aspects, the Fc receptor is an Fcy receptor. In one aspect, the Fc receptor is a human Fc receptor. In one aspect, the Fc receptor is an activating Fc receptor. In specific aspects, the Fc receptor is an activating human Fcy receptor, more specifically human FcyRIIIa, FcyRI, or FcyRIIa, most specifically human FcyRIIIa. Preferably, binding to each of these receptors is reduced. In one aspect, the binding affinity to a complement component, in particular the specific binding affinity to Clq, is also reduced. In one aspect, the binding affinity to the neonatal Fc receptor (FcRn) is not reduced.

[0203] Essentially similar binding to FcRn is achieved when the Fc domain (or antigen binding molecule comprising the Fc domain) exhibits greater than about 70% of the binding affinity of a non-engineered form of the Fc domain (or antigen binding molecule comprising the non-engineered form of the Fc domain) to FcRn, i.e., the binding affinity of the Fc domain to the receptor is maintained. The Fc domain or antigen binding molecule of the application comprising the Fc domain can exhibit greater than about 80% or even greater than about 90% of this affinity. In certain aspects, the Fc domain of the antigen binding molecule is engineered to have reduced effector function as compared to a non-engineered Fc domain. Reduced effector function can include, but is not limited to, one or more of the following: reduced complement dependent cytotoxicity (CDC), reduced antibody dependent cell-mediated cytotoxicity (ADCC), reduced antibody dependent cellular phagocytosis (ADCP), decreased cytokine secretion, decreased immune complex-mediated antigen presentation cell uptake of antigen, decreased binding to NK cells, decreased binding to macrophages, decreased binding to monocytes, decreased binding to polymorphonuclear cells, decreased direct signaling-induced apoptosis, decreased cross-linking of target-bound antibodies, decreased dendritic cell maturation, or decreased T cell priming. In one aspect, the reduced effector function is one or more reduced effector functions selected from the group of reduced CDC, reduced ADCC, reduced ADCP, and decreased cytokine secretion. In a particular aspect, the reduced effector function is reduced ADCC. In one aspect, the reduced ADCC is less than 20% of the ADCC induced by a non-engineered Fc domain (or binding molecule comprising a non-engineered Fc domain).

[0204] In one aspect, the amino acid mutation that reduces the binding affinity of the Fc domain to an Fc receptor and / or effector function is an amino acid substitution. In one aspect, the Fc domain comprises an amino acid substitution at a position selected from the group comprising E233, L234, L235, N297, P331, and P329 (numbering according to Kabat EU index). In a more particular aspect, the Fc domain comprises an amino acid substitution at a position selected from the group comprising L234, L235, and P329 (numbering according to Kabat EU index). In one aspect, the Fc domain comprises the amino acid substitutions L234A and L235A (numbering according to Kabat EU index). In some such aspects, the Fc domain is an IgGl Fc domain, in particular a human IgGl Fc domain. In one aspect, the Fc domain comprises an amino acid substitution at position P329. In a more particular aspect, the amino acid substitution is P329A or P329G, in particular P329G (numbering according to Kabat EU index). In one aspect, the Fc domain comprises an amino acid substitution at position P329 and an additional amino acid substitution at a position selected from E233, L234, L235, N297, and P331 (numbering according to Kabat EU index). In a more particular aspect, the additional amino acid substitution is E233P, L234A, L235A, L235E, N297A, N297D, or P331S. In a particular aspect, the Fc domain comprises amino acid substitutions at positions P329, L234, and L235 (numbering according to Kabat EU index). In a more particular aspect, the Fc domain comprises the amino acid mutations L234A, L235A, and P329G (“P329G LALA”, “PGLALA”, or “LALAPG”). Specifically, in a particular aspect, each subunit of the Fc domain comprises the amino acid substitutions L234A, L235A, and P329G (numbering according to Kabat EU index), i.e. in each of the first and second subunit of the Fc domain, the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced with a glycine residue (P329G) (numbering according to Kabat’s EU index).

[0205] In some such aspects, the Fc domain is an IgGl Fc domain, particularly a human IgGl Fc domain. The "P329G LALA" combination of amino acid substitutions almost completely eliminates Fc receptor (and complement) binding of a human IgGl Fc domain, as described in PCT Publication No. WO 2012 / 130831, the entire contents of which are incorporated herein by reference. WO 2012 / 130831 also describes methods of making such mutant Fc domains and methods of determining their properties, such as Fc receptor binding or effector function.

[0206] In comparison to IgGl antibodies, IgG4 antibodies exhibit reduced binding affinity to Fc receptors and reduced effector function. Thus, in one aspect, the Fc domain of the binding molecules of the application is an IgG4 Fc domain, particularly a human IgG4 Fc domain. In one aspect, the IgG4 Fc domain comprises an amino acid substitution at position S228, particularly the amino acid substitution S228P (numbering according to the Kabat EU index). To further reduce its binding affinity to Fc receptors and / or its effector function, in one aspect, the IgG4 Fc domain comprises an amino acid substitution at position L235, particularly the amino acid substitution L235E (numbering according to the Kabat EU index). In one aspect, the IgG4 Fc domain comprises an amino acid substitution at position P329, particularly the amino acid substitution P329G (numbering according to the Kabat EU index). In a preferred aspect, the IgG4 Fc domain comprises amino acid substitutions at positions S228, L235 and P329, particularly the amino acid substitutions S228P, L235E and P329G (numbering according to the Kabat EU index). Such IgG4 Fc domain mutants and their Fc gamma receptor binding properties are described in PCT Publication No. WO 2012 / 130831, the entire contents of which are incorporated herein by reference.

[0207] In particular aspects, the Fc domain exhibiting reduced binding affinity to Fc receptors and / or reduced effector function in comparison to a native IgGl Fc domain is a human IgGl Fc domain comprising the amino acid substitutions L234A, L235A and optionally P329G, or a human IgG4 Fc domain comprising the amino acid substitutions S228P, L235E and optionally P329G (numbering according to the EU index of Kabat).

[0208] In certain aspects, the N-glycosylation of the Fc domain has been eliminated. In some such aspects, the Fc domain comprises an amino acid mutation at position N297, particularly an amino acid substitution that replaces the asparagine with alanine (N297A) or aspartic acid (N297D) (numbering according to the EU index of Kabat).

[0209] In addition to the Fc domains described above and in PCT Publication No. WO 2012 / 130831, Fc domains with reduced Fc receptor binding and / or reduced effector function include those Fc domains with substitution of one or more of Fc domain residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Patent No. 6,737,056) (numbering according to the EU index of Kabat). Such Fc mutants include Fc mutants with substitutions at two or more of amino acids at positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutant, which has residues 265 and 297 substituted to alanine (U.S. Patent No. 7,332,581).

[0210] Mutant Fc domains can be prepared by amino acid deletion, substitution, insertion, or modification using genetic or chemical methods well known in the art. Genetic methods can include site-specific mutagenesis of coding DNA sequences, PCR, gene synthesis, and the like. Correct nucleotide changes can be verified, e.g., by sequencing.

[0211] Binding to Fc receptors can be readily determined, e.g., by ELISA or by surface plasmon resonance (SPR) using standard instruments such as a BIAcore instrument (GE Healthcare), and Fc receptors such as can be obtained by recombinant expression. Alternatively, cell lines known to express particular Fc receptors, such as human NK cells expressing Fcyllla receptors, can be used to assess the binding affinity of an Fc domain or binding molecule comprising an Fc domain to an Fc receptor.

[0212] Effector function of an Fc domain or a binding molecule comprising an Fc domain can be measured by methods known in the art. Examples of in vitro assays for assessing ADCC activity of a molecule of interest are described in U.S. Patent No. 5,500,362; Hellstrom et al., Proc Natl Acad Sci USA 83, 7059-7063 (1986) and Hellstrom et al., Proc Natl Acad Sci USA 82, 1499-1502 (1985); U.S. Patent No. 5,821,337; Bruggemann et al., J Exp Med 166, 1351-1361 (1987).

[0213] Alternatively, non-radioactive assays can be used (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA); and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.

[0214] Alternatively or additionally, ADCC activity of a molecule of interest can be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al., Proc Natl Acad Sci USA 95, 652-656 (1998).

[0215] In one aspect, the Fc domain has reduced binding to a complement component, in particular Clq. Thus, in one aspect, wherein the Fc domain is engineered to have reduced effector function, the reduced effector function includes reduced CDC. Clq binding assays can be conducted to determine whether a Fc domain or binding molecule comprising an Fc domain is capable of binding Clq and hence has CDC activity. See, e.g., Clq and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al., J Immunol Methods 202, 163 (1996); Cragg et al., Blood 101, 1045-1052 (2003); and Cragg and Glennie, Blood 103, 2738-2743 (2004)).

[0216] FcRn binding and in vivo clearance / half-life determination can also be performed using methods known in the art (see, e.g., Petkova, S.B. et al., Int'l. Immunol. 18(12): 1759-1769 (2006); WO 2013 / 120929).

[0217] Configuration of antigen binding molecules

[0218] The antigen binding molecules according to the application can have various molecular configurations, i.e. the domains of the binding molecules can be connected to each other in different ways.

[0219] The antigen binding molecule can comprise a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the cytokine receptor binding domain is fused at its C-terminus to the N-terminus of the target binding domain, and the target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits. The target binding domain can be a Fab molecule. Thus, the cytokine receptor binding domain can be fused to the VH or VL domain of the target binding domain. In one embodiment, the antigen binding molecule comprises a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the target binding domain is a Fab molecule, and wherein the cytokine receptor binding domain is fused at its C-terminus to the N-terminus of the VH domain of the target binding domain, and the target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits (schematic see, e.g., Figures 1 IB, 11C, 11F, and 11G). In one embodiment, the antigen binding molecule comprises a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the target binding domain is a Fab molecule, and wherein the cytokine receptor binding domain is fused at its C-terminus to the N-terminus of the VL domain of the target binding domain, and the target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits (schematic see, e.g., Figures 11D, 11E, 11H, and 11I).

[0220] The antigen binding molecule can comprise a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the target binding domain is fused at its C-terminus to the N-terminus of a first Fc domain subunit, and the cytokine receptor binding domain is fused at its C-terminus to the N-terminus of a second Fc domain subunit (schematic see, e.g., Figures 13A, 13B, 13C, and 13D).

[0221] The antigen binding molecule can comprise a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits, and the cytokine receptor binding domain is fused at its N-terminus to the C-terminus of the same Fc domain subunit (see e.g. Figures 13E, 13F, 13G, and 13H for schematic).

[0222] The cytokine receptor binding domain can be fused via a peptide linker. The peptide linker can comprise an amino acid sequence according to SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 279, SEQ ID NO: 280, or SEQ ID NO: 281.

[0223] Antigen binding molecule pairs

[0224] In one aspect, both antigen binding molecules of the pair of antigen binding molecules comprise a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the cytokine receptor binding domain is fused at its C-terminus to the N-terminus of the target binding domain, and the target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits.

[0225] In one aspect, the target binding domain of the antigen binding molecule is a Fab molecule. Thus, in one aspect, the pair of antigen binding molecules comprises a first antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising in sequence from N-terminus to C-terminus a first cytokine receptor binding domain, a VH1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising in sequence from N-terminus to C-terminus a VL1 and a CL1; and a second antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising in sequence from N-terminus to C-terminus a second cytokine receptor binding domain, a VH2, a CH12, and a second Fc domain subunit; and a third polypeptide comprising in sequence from N-terminus to C-terminus a VL2 and a CL2.

[0226] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a VH1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL1, and a CL1; and a second antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH2, a CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a VL2, and a CL2.

[0227] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a VH1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL1, and a CL1; and a second antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH2, a CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a VL2, and a CL2.

[0228] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a VL1, a CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VH1, and a CL1; and a second antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a VH2, a CH12, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL2, and a CL2.

[0229] In one aspect, the pair of antigen binding molecules comprises a first antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VL1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, VH1, and CL1; and a second antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH2, CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, VL2, and CL2.

[0230] In one aspect, the pair of antigen binding molecules comprises a first antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, VL1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, VH1, and CL1; and a second antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH2, CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, VL2, and CL2.

[0231] In one aspect, the pair of antigen binding molecules comprises a first antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VL1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, VH1, and CL1; and a second antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, VH2, CH12, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, VL2, and CL2.

[0232] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 27; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 30; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0233] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 38; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 37; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0234] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 31; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 33.

[0235] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 27; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 33.

[0236] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 27; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 33.

[0237] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 30; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 31.

[0238] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 38; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 36.

[0239] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 37; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 35.

[0240] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 260; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 259; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127.

[0241] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 256; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 122; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 255.

[0242] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 261; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 258; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127.

[0243] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 257; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 254.

[0244] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 260; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 255.

[0245] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 256; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 259; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127.

[0246] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 261 ; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 254.

[0247] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 257; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 258; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127.

[0248] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 86; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 83; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 87.

[0249] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 92; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 91.

[0250] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 95; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 101; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0251] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 99; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 102.

[0252] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 97; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 103; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0253] In one aspect, the pair of antigen binding molecules comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 100; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 104.

[0254] In one aspect, the pair of antigen binding molecules comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 99; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 101 ; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0255] In one aspect, the pair of antigen binding molecules comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 95; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 102.

[0256] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 100; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 103; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0257] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 97; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 104.

[0258] In an aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 110; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 113; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0259] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 105; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 109.

[0260] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 111; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0261] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 107; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 108.

[0262] In one aspect, the pair of antigen binding molecules comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 110; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 109.

[0263] In one aspect, the pair of antigen binding molecules comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 105; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 113; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0264] In one aspect, the pair of antigen binding molecules comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 111; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 108.

[0265] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 107; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0266] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 125; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 129; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127.

[0267] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 118; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 122; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 123.

[0268] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 126; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 128; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127.

[0269] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 120; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 122; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 121.

[0270] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 125; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 122; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 123.

[0271] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 118; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 129; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127.

[0272] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 126; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 122; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 121.

[0273] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 120; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 128; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127.

[0274] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 136; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 134; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 138; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 137.

[0275] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 135; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 134; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 138; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 139.

[0276] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 146; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 144; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 148; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 147.

[0277] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 145; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 144; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 148; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 149.

[0278] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163.

[0279] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159.

[0280] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163.

[0281] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 162; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 157.

[0282] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161 ; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163.

[0283] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159.

[0284] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 162; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163.

[0285] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 157.

[0286] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 194; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 193; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0287] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 195; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0288] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 196; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0289] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 197; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0290] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 198; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0291] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 199; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0292] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 200; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0293] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 201 ; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0294] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 202; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0295] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 204; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0296] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 204; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0297] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 205; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.

[0298] In one aspect, the two antigen binding molecules of the antigen binding molecule pair each comprise a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the target binding domain is fused at its C-terminus to the N-terminus of a first Fc domain subunit and the cytokine receptor binding domain is fused at its C-terminus to the N-terminus of a second Fc domain subunit. In one aspect, the two antigen binding molecules of the antigen binding molecule pair each comprise a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the target binding domain is fused at its C-terminus to the N-terminus of a first Fc domain subunit and the cytokine receptor binding domain is fused at its C-terminus to the N-terminus of a second Fc domain subunit, wherein the target binding domain is a Fab molecule. In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising, in order from N-terminus to C-terminus, VH1, CH11, and a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VL1, and CL1; and a third polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain and a second Fc domain subunit; and a second antigen binding molecule comprising: a first polypeptide comprising, in order from N-terminus to C-terminus, VH2, CH12, and a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VL2, and CL2; and a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain and a second Fc domain subunit.

[0299] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising, in order from N-terminus to C-terminus, VL1, CH11, and a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH1, and CL1; and a third polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain and a second Fc domain subunit; and a second antigen binding molecule comprising: a first polypeptide comprising, in order from N-terminus to C-terminus, VH2, CH12, and a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VL2, and CL2; and a third polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain and a second Fc domain subunit.

[0300] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 32; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 39; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 34; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 40.

[0301] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 34; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 39; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 32; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 40.

[0302] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 237; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 238; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0303] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 235; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 236; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0304] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 239; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 240; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0305] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 235; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 237; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0306] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 236; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 235; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0307] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 240; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 239; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0308] In one aspect, both antigen binding molecules of the antigen binding molecule pair comprise a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits and the cytokine receptor binding domain is fused at its N-terminus to the C-terminus of the same Fc domain subunit.

[0309] Thus, in one aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first target binding domain fused at its C-terminus to the N-terminus of one of the Fc domain subunits and a first cytokine receptor binding domain fused at its N-terminus to the C-terminus of the same Fc domain subunit; and a second antigen binding molecule comprising a second target binding domain fused at its C-terminus to the N-terminus of one of the Fc domain subunits and a second cytokine receptor binding domain fused at its N-terminus to the C-terminus of the same Fc domain subunit.

[0310] In one aspect, the target binding domain of one of the antigen binding molecules is a cross-Fab molecule. Thus, in one embodiment, the pair of antigen binding molecules comprises: a first antigen binding molecule comprising a target binding domain fused at the C-terminus of its CH11 to the N-terminus of one of the Fc domain subunits and a first cytokine receptor binding domain fused at its N-terminus to the C-terminus of the same Fc domain subunit; and a second antigen binding molecule comprising a target binding domain fused at the C-terminus of its CL2 to the N-terminus of one of the Fc domain subunits and a second cytokine receptor binding domain fused at its N-terminus to the C-terminus of the same Fc domain subunit. In one embodiment, the pair of antigen binding molecules comprises: a first antigen binding molecule comprising a target binding domain fused at the C-terminus of its CL1 to the N-terminus of one of the Fc domain subunits and a first cytokine receptor binding domain fused at its N-terminus to the C-terminus of the same Fc domain subunit; and a second antigen binding molecule comprising a target binding domain fused at the C-terminus of its CH12 to the N-terminus of one of the Fc domain subunits and a second cytokine receptor binding domain fused at its N-terminus to the C-terminus of the same Fc domain subunit.

[0311] In one aspect, the target binding domain of one of the antigen binding molecules is a cross-Fab molecule. Thus, in one embodiment, the pair of antigen binding molecules comprises: a first antigen binding molecule comprising a target binding domain fused at the C-terminus of its CH11 to the N-terminus of one of the Fc domain subunits and a first cytokine receptor binding domain fused at its N-terminus to the C-terminus of the same Fc domain subunit; and a second antigen binding molecule comprising a target binding domain fused at the C-terminus of its CL2 to the N-terminus of one of the Fc domain subunits and a second cytokine receptor binding domain fused at its N-terminus to the C-terminus of the same Fc domain subunit. In one embodiment, the pair of antigen binding molecules comprises: a first antigen binding molecule comprising a target binding domain fused at the C-terminus of its CL1 to the N-terminus of one of the Fc domain subunits and a first cytokine receptor binding domain fused at its N-terminus to the C-terminus of the same Fc domain subunit; and a second antigen binding molecule comprising a target binding domain fused at the C-terminus of its CH12 to the N-terminus of one of the Fc domain subunits and a second cytokine receptor binding domain fused at its N-terminus to the C-terminus of the same Fc domain subunit.

[0312] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VL1, a CH11, a second Fc domain subunit, and a first cytokine receptor binding domain; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VH1, and a CL1; and a second antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH2, a CH12, a second Fc domain subunit, and a second cytokine receptor binding domain; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL2, and a CL2.

[0313] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VL1, a CH11, a second Fc domain subunit, and a first cytokine receptor binding domain; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VH1, and a CL1; and a second antigen binding molecule comprising: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, a VH2, a CH12, a second Fc domain subunit, and a second cytokine receptor binding domain; and a third polypeptide comprising, in order from N-terminus to C-terminus, a VL2, and a CL2.

[0314] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 42; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 41; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 45; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 43.

[0315] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 46; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 41; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 47; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 43.

[0316] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 246; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 249; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0317] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 242; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 245; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0318] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 250; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 253; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0319] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 248; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 247; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0320] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 244; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 243; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0321] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 252; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 251; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0322] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 42; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 42; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 245; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29.

[0323] Alternative configurations of antigen binding molecules

[0324] The antigen binding molecule can comprise a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the cytokine receptor binding domain is fused at its C-terminus to the N-terminus of the target binding domain, and the target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits, wherein the target binding domain is a VHH domain. Thus, the antigen binding molecule can comprise: a first polypeptide comprising a first Fc domain subunit; and a second polypeptide comprising, in order from N-terminus to C-terminus, a first cytokine receptor binding domain, a first target binding domain, and a second Fc domain subunit; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; and a second polypeptide comprising, in order from N-terminus to C-terminus, a second cytokine receptor binding domain, a second target binding domain, and a second Fc domain subunit.

[0325] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 173; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 171.

[0326] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 176; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 172.

[0327] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 175; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 171.

[0328] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 176; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 174.

[0329] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 175; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 170.

[0330] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 173; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 170.

[0331] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 176; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28 and a second polypeptide comprising the amino acid sequence of SEQ ID NO: 172.

[0332] The antigen binding molecule can comprise a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the cytokine receptor binding domain is fused at its C-terminus to the N-terminus of the target binding domain, and the target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits, wherein the cytokine receptor binding domain is a Fab molecule.

[0333] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 267, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 268, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 265; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 272, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 271.

[0334] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 267, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 268, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 265; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 274, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 273.

[0335] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 269, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 265, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 268; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 272, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 271.

[0336] In an aspect, the antigen binding molecule pair comprises: a first antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 269, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 265, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 268; and a second antigen binding molecule comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 274, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 273.

[0337] The antigen binding molecule can comprise a target binding domain, a cytokine receptor binding domain, and an Fc domain, wherein the cytokine receptor binding domain is fused at its C-terminus to the N-terminus of the target binding domain, and the target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits, wherein the cytokine receptor binding domain is a scFv domain.

[0338] In one aspect, the antigen binding molecule pair comprises a first antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 276; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 275; and a second antigen binding molecule comprising: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 277; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 278.

[0339] Specific embodiments of the invention

[0340] Specific embodiments of the application are listed below.

[0341] 1. An antigen binding molecule pair that specifically binds to a target antigen, the antigen binding molecule pair comprising: a) a first antigen binding molecule comprising i) a first target binding domain, ii) a first cytokine receptor binding domain, and iii) an Fc domain; and b) a second antigen binding molecule comprising i) a second target binding domain, ii) a second cytokine receptor binding domain, and iii) an Fc domain; wherein the first target binding domain is capable of binding to a first epitope on the target antigen and the second target binding domain is capable of binding to a second epitope on the target antigen, wherein the first target binding domain and the second target binding domain do not compete for binding on the target antigen; and wherein the first cytokine receptor binding domain is capable of binding to a first cytokine receptor subunit, and the second cytokine receptor binding domain is capable of binding to a second cytokine receptor subunit.

[0342] 2. The antigen binding molecule pair according to embodiment 1, wherein the first target binding domain and the second target binding domain are antibody fragments, such as Fv, Fab, scFv, scFab molecules or single domain antibodies.

[0343] 3. The pair of antigen binding molecules according to embodiment 1 or 2, wherein the first target binding domain and the second target binding domain are Fab molecules.

[0344] 4. The pair of antigen binding molecules according to embodiment 3, wherein the first target binding domain comprises a heavy chain variable domain (VH1), a light chain variable domain (VL1), a heavy chain constant domain (CH11), and a light chain constant domain (CL1), and wherein the second target binding domain comprises a heavy chain variable domain (VH2), a light chain variable domain (VL2), a heavy chain constant domain (CH12), and a light chain constant domain (CL2).

[0345] 5. The pair of antigen binding molecules according to embodiment 3 or 4, wherein the first target binding domain and / or the second target binding domain are cross-Fab molecules.

[0346] 6. The pair of antigen binding molecules according to any one of the preceding embodiments, wherein the first target binding domain and the second target binding domain specifically bind to a tumor associated antigen or a T cell antigen.

[0347] 7. The pair of antigen binding molecules according to any one of the preceding embodiments, wherein the first target binding domain and the second target binding domain specifically bind to FAP, PD-1, Her2, Her3, LAG-3, or EGFR.

[0348] 8. The antigen binding molecule pair according to any of the preceding embodiments, wherein a) the first target binding domain comprises a VH1 of SEQ ID NO: 20 and a VL1 of SEQ ID NO: 21 and the second target binding domain comprises a VH2 of SEQ ID NO: 22 and a VL2 of SEQ ID NO: 23, or b) the first target binding domain comprises a VH1 of SEQ ID NO: 22 and a VL1 of SEQ ID NO: 23 and the second target binding domain comprises a VH2 of SEQ ID NO: 20 and a VL2 of SEQ ID NO: 21, or c) the first target binding domain comprises a VH1 of SEQ ID NO: 76 and a VL1 of SEQ ID NO: 77 and the second target binding domain comprises a VH2 of SEQ ID NO: 78 and a VL2 of SEQ ID NO: 79, or d) the first target binding domain comprises a VH1 of SEQ ID NO: 78 and a VL1 of SEQ ID NO: 79 and the second target binding domain comprises a VH2 of SEQ ID NO: 76 and a VL2 of SEQ ID NO: 77; or e) the first target binding domain comprises a VH1 of SEQ ID NO: 93 and a VL1 of SEQ ID NO: 94 and the second target binding domain comprises a VH2 of SEQ ID NO: 78 and a VL2 of SEQ ID NO: 79; or f) the first target binding domain comprises a VH1 of SEQ ID NO: 78 and a VL1 of SEQ ID NO: 79 and the second target binding domain comprises a VH2 of SEQ ID NO: 93 and a VL2 of SEQ ID NO: 94, or g) the first target binding domain comprises a VH1 of SEQ ID NO: 130 and a VL1 of SEQ ID NO: 131 and the second target binding domain comprises a VH2 of SEQ ID NO: 132 and a VL2 of SEQ ID NO: 133; or h) the first target binding domain comprises a VH1 of SEQ ID NO: 132 and a VL1 of SEQ ID NO: 133 and the second target binding domain comprises a VH2 of SEQ ID NO: 130 and a VL2 of SEQ ID NO: 131.or i) the first target binding domain comprises a VH1 of SEQ ID NO: 140 and a VL1 of SEQ ID NO: 141 and the second target binding domain comprises a VH2 of SEQ ID NO: 142 and a VL2 of SEQ ID NO: 143; or j) the first target binding domain comprises a VH1 of SEQ ID NO: 142 and a VL1 of SEQ ID NO: 143 and the second target binding domain comprises a VH2 of SEQ ID NO: 140 and a VL2 of SEQ ID NO: 141; or k) the first target binding domain comprises a VH1 of SEQ ID NO: 114 and a VL1 of SEQ ID NO: 115 and the second target binding domain comprises a VH2 of SEQ ID NO: 116 and a VL2 of SEQ ID NO: 117; or l) the first target binding domain comprises a VH1 of SEQ ID NO: 116 and a VL1 of SEQ ID NO: 117 and the second target binding domain comprises a VH2 of SEQ ID NO: 114 and a VL2 of SEQ ID NO: 115; or m) the first target binding domain comprises a VH1 of SEQ ID NO: 150 and a VL1 of SEQ ID NO: 151 and the second target binding domain comprises a VH2 of SEQ ID NO: 152 and a VL2 of SEQ ID NO: 153; or n) the first target binding domain comprises a VH1 of SEQ ID NO: 152 and a VL1 of SEQ ID NO: 153 and the second target binding domain comprises a VH2 of SEQ ID NO: 150 and a VL2 of SEQ ID NO: 151.

[0349] 9. The pair of antigen binding molecules of any of the preceding embodiments, wherein the first cytokine receptor subunit and the second cytokine receptor subunit are both subunits of an IFNy receptor complex or an IL-2 receptor complex or an IL-7 receptor complex.

[0350] 10. The pair of antigen binding molecules according to any one of the preceding embodiments, wherein a) the first cytokine receptor binding domain is capable of binding IFNyRl and the second cytokine receptor binding domain is capable of binding IFNyR2, or b) the first cytokine receptor binding domain is capable of binding IFNyR2 and the second cytokine receptor binding domain is capable of binding IFNyRl ; or c) the first cytokine receptor binding domain is capable of binding IL-2Rß and the second cytokine receptor binding domain is capable of binding IL-2Ry, or d) the first cytokine receptor binding domain is capable of binding IL-2Ry and the second cytokine receptor binding domain is capable of binding IL-2Rß; or e) the first cytokine receptor binding domain is capable of binding IL-2Ry and the second cytokine receptor binding domain is capable of binding IL-7Ra; or f) the first cytokine receptor binding domain is capable of binding IL-7Ra and the second cytokine receptor binding domain is capable of binding IL-2Ry.

[0351] 11. The pair of antigen binding molecules according to any one of the preceding embodiments, wherein the first and second cytokine receptor binding domains are antibody fragments, such as Fv, Fab, scFv, scFab or single domain antibodies.

[0352] 12. The pair of antigen binding molecules according to any one of the preceding embodiments, wherein the first and second cytokine receptor binding domains are VHH domains.

[0353] 13. The antigen binding molecule pair according to any of the preceding embodiments, wherein a) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 5, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, or b) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 5, or c) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58 SEQ ID NO: 60, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65, or d) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58 SEQ ID NO: 60.or e) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65; or f) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192.

[0354] 14. The pair of antigen binding molecules according to any one of the preceding embodiments, wherein a) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 3 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 7, or b) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 7 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 3; or c) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 60 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, or d) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 60; or e) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 186 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, or f) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 186.

[0355] 15. The pair of antigen binding molecules according to any one of the preceding embodiments, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule comprises a first Fc domain subunit and a second Fc domain subunit.

[0356] 16. The pair of antigen binding molecules according to any one of the preceding embodiments, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule is an IgG Fc domain, in particular an IgGl Fc domain.

[0357] 17. The pair of antigen binding molecules according to any one of the preceding embodiments, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule is a human Fc domain.

[0358] 18. The pair of antigen binding molecules according to any one of the preceding embodiments, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule comprises a modification that promotes association of the first subunit with the second subunit of the Fc domain.

[0359] 19. The pair of antigen binding molecules according to any of the preceding embodiments, wherein the Fc domain of the first and the second antigen binding molecule comprises one or more amino acid substitution that reduces binding to an Fc receptor and / or effector function.

[0360] 20. The pair of antigen binding molecules according to any of the preceding embodiments, wherein the cytokine receptor binding domain is fused to their respective fusion point via a peptide linker.

[0361] 21. The pair of antigen binding molecules according to embodiment 20, wherein the peptide linker comprises an amino acid sequence selected from SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 279, SEQ ID NO: 280, or SEQ ID NO: 281.

[0362] 22. The pair of antigen binding molecules according to any of the preceding embodiments, wherein the first cytokine receptor binding domain is fused at its C-terminus to the N-terminus of VH1 or VL1 of the first target binding domain, and the second cytokine receptor binding domain is fused at its C-terminus to the N-terminus of VH2 or VL2 of the second target binding domain.

[0363] 23. The antigen binding molecule pair of any of the preceding embodiments, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, the first cytokine receptor binding domain, VH1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, VL1, and CL1; and the sec...

Claims

1. A pair of antigen binding molecules that specifically bind to a target antigen, the pair of antigen binding molecules comprising: a) a first antigen binding molecule comprising i) a first target binding domain, ii) a first cytokine receptor binding domain, and iii) an Fc domain; and b) a second antigen binding molecule comprising i) a second target binding domain, ii) a second cytokine receptor binding domain, and iii) an Fc domain; wherein the first target binding domain is capable of binding to a first epitope on the target antigen and the second target binding domain is capable of binding to a second epitope on the target antigen, wherein the first and second target binding domains do not compete for binding on the target antigen; and wherein the first cytokine receptor binding domain is capable of binding to a first cytokine receptor subunit, and the second cytokine receptor binding domain is capable of binding to a second cytokine receptor subunit.

2. The pair of antigen binding molecules according to claim 1, wherein the first and second target binding domains are antibody fragments, such as Fv, Fab, scFv, scFab molecules or single domain antibodies.

3. The pair of antigen binding molecules according to claim 1 or 2, wherein the first and second target binding domains are Fab molecules.

4. The pair of antigen binding molecules according to claim 3, wherein the first target binding domain comprises a heavy chain variable domain (VH1), a light chain variable domain (VL1), a heavy chain constant domain (CH11), and a light chain constant domain (CL1), and wherein the second target binding domain comprises a heavy chain variable domain (VH2), a light chain variable domain (VL2), a heavy chain constant domain (CH12), and a light chain constant domain (CL2).

5. The pair of antigen binding molecules according to claim 3 or 4, wherein the first and / or second target binding domain is a cross-Fab molecule.

6. The pair of antigen binding molecules according to any one of the preceding claims, wherein the first and second target binding domains specifically bind to a tumor associated antigen or a T cell antigen.

7. The pair of antigen binding molecules according to any one of the preceding claims, wherein the first and second target binding domains specifically bind to FAP, PD-1, Her2, Her3, LAG-3, or EGFR.

8. The pair of antigen binding molecules according to any one of the preceding claims, wherein a) the first target binding domain comprises a VH1 of SEQ ID NO: 20 and a VL1 of SEQ ID NO: 21 and the second target binding domain comprises a VH2 of SEQ ID NO: 22 and a VL2 of SEQ ID NO: 23, or b) the first target binding domain comprises a VH1 of SEQ ID NO: 22 and a VL1 of SEQ ID NO: 23 and the second target binding domain comprises a VH2 of SEQ ID NO: 20 and a VL2 of SEQ ID NO: 21, or c) the first target binding domain comprises a VH1 of SEQ ID NO: 76 and a VL1 of SEQ ID NO: 77 and the second target binding domain comprises a VH2 of SEQ ID NO: 78 and a VL2 of SEQ ID NO: 79, or d) the first target binding domain comprises a VH1 of SEQ ID NO: 78 and a VL1 of SEQ ID NO: 79 and the second target binding domain comprises a VH2 of SEQ ID NO: 76 and a VL2 of SEQ ID NO: 77; or e) the first target binding domain comprises a VH1 of SEQ ID NO: 93 and a VL1 of SEQ ID NO: 94 and the second target binding domain comprises a VH2 of SEQ ID NO: 78 and a VL2 of SEQ ID NO: 79; or f) the first target binding domain comprises a VH1 of SEQ ID NO: 78 and a VL1 of SEQ ID NO: 79 and the second target binding domain comprises a VH2 of SEQ ID NO: 93 and a VL2 of SEQ ID NO: 94, or g) the first target binding domain comprises a VH1 of SEQ ID NO: 130 and a VL1 of SEQ ID NO: 131 and the second target binding domain comprises a VH2 of SEQ ID NO: 132 and a VL2 of SEQ ID NO: 133; or h) the first target binding domain comprises a VH1 of SEQ ID NO: 132 and a VL1 of SEQ ID NO: 133 and the second target binding domain comprises a VH2 of SEQ ID NO: 130 and a VL2 of SEQ ID NO: 131; or i) the first target binding domain comprises a VH1 of SEQ ID NO: 140 and a VL1 of SEQ ID NO: 141 and the second target binding domain comprises a VH2 of SEQ ID NO: 142 and a VL2 of SEQ ID NO: 143; or j) the first target binding domain comprises a VH1 of SEQ ID NO: 142 and a VL1 of SEQ ID NO: 143 and the second target binding domain comprises a VH2 of SEQ ID NO: 140 and a VL2 of SEQ ID NO: 141; or k) the first target binding domain comprises a VH1 of SEQ ID NO: 114 and a VL1 of SEQ ID NO: 115 and the second target binding domain comprises a VH2 of SEQ ID NO: 116 and a VL2 of SEQ ID NO: 117; or l) the first target binding domain comprises a VH1 of SEQ ID NO: 116 and a VL1 of SEQ ID NO: 117 and the second target binding domain comprises a VH2 of SEQ ID NO: 114 and a VL2 of SEQ ID NO: 115; or m) the first target binding domain comprises a VH1 of SEQ ID NO: 150 and a VL1 of SEQ ID NO: 151 and the second target binding domain comprises a VH2 of SEQ ID NO: 152 and a VL2 of SEQ ID NO: 153; or n) the first target binding domain comprises a VH1 of SEQ ID NO: 152 and a VL1 of SEQ ID NO: 153 and the second target binding domain comprises a VH2 of SEQ ID NO: 150 and a VL2 of SEQ ID NO:

151.

9. The pair of antigen binding molecules of any of the preceding claims, wherein the first cytokine receptor subunit and the second cytokine receptor subunit are both subunits of an IFNy receptor complex or an IL-2 receptor complex or an IL-7 receptor complex.

10. The pair of antigen binding molecules of any of the preceding claims, wherein a) the first cytokine receptor binding domain is capable of binding IFNyRl and the second cytokine receptor binding domain is capable of binding IFNyR2, or b) the first cytokine receptor binding domain is capable of binding IFNyR2 and the second cytokine receptor binding domain is capable of binding IFNyRl; or c) the first cytokine receptor binding domain is capable of binding IL-2Rβ and the second cytokine receptor binding domain is capable of binding IL-2Rγ, or d) the first cytokine receptor binding domain is capable of binding IL-2Rγ and the second cytokine receptor binding domain is capable of binding IL-2Rβ; or e) the first cytokine receptor binding domain is capable of binding IL-2Rγ and the second cytokine receptor binding domain is capable of binding IL-7Rα; or f) the first cytokine receptor binding domain is capable of binding IL-7Rα and the second cytokine receptor binding domain is capable of binding IL-2Rγ.

11. The pair of antigen binding molecules according to any one of the preceding claims, wherein the first and second cytokine receptor binding domains are antibody fragments, such as Fv, Fab, scFv, scFab or a single domain antibody.

12. The pair of antigen binding molecules according to any one of the preceding claims, wherein the first and second cytokine receptor binding domains are VHH domains.

13. The pair of antigen binding molecules according to any one of the preceding claims, wherein a) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 5 and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, or b) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10 and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 5; or c) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58 SEQ ID NO: 60 and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64 and SEQ ID NO: 65; or d) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64 and SEQ ID NO: 65 and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58 SEQ ID NO: 60; or e) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192 and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65; or f) the first cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65 and the second cytokine receptor binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO:

192.

14. The pair of antigen binding molecules of any of the preceding claims, wherein a) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 3 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 7, or b) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 7 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 3; or c) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 60 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, or d) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 60; or e) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 186 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62, or f) the first cytokine receptor binding domain comprises the sequence of SEQ ID NO: 62 and the second cytokine receptor binding domain comprises the sequence of SEQ ID NO:

186.

15. The pair of antigen binding molecules according to any one of the preceding claims, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule comprises a first Fc domain subunit and a second Fc domain subunit.

16. The pair of antigen binding molecules according to any one of the preceding claims, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule is an IgG Fc domain, in particular an IgGl Fc domain.

17. The pair of antigen binding molecules according to any one of the preceding claims, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule is a human Fc domain.

18. The pair of antigen binding molecules according to any one of the preceding claims, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule comprises a modification that promotes association of the first and second subunit of the Fc domain.

19. The pair of antigen binding molecules according to any one of the preceding claims, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule comprises one or more amino acid substitution that reduces binding to an Fc receptor and / or effector function.

20. The pair of antigen binding molecules according to any one of the preceding claims, wherein the cytokine receptor binding domains are fused to their respective fusion point via a peptide linker.

21. The pair of antigen-binding molecules of claim 20, wherein the peptide linker comprises an amino acid sequence selected from SEQ ID NO: 262, SEQ ID NO: 263, SEQ ID NO: 264, SEQ ID NO: 279, SEQ ID NO: 280, or SEQ ID NO:

281.

22. The pair of antigen-binding molecules of any of the preceding claims, wherein the first cytokine receptor binding domain is fused at its C-terminus to the N-terminus of VH1 or VL1 of the first target binding domain, and the second cytokine receptor binding domain is fused at its C-terminus to the N-terminus of VH2 or VL2 of the second target binding domain.

23. The pair of antigen-binding molecules of any of the preceding claims, wherein a) the first antigen-binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, the first cytokine receptor binding domain, VH1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, VL1 and CL1; and the second antigen-binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, the second cytokine receptor binding domain, VH2, CH12, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, VL2 and CL2; or b) the first antigen-binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, the first cytokine receptor binding domain, VL1, and CL1; and the second antigen-binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH2, CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, the second cytokine receptor binding domain, VL2, and CL2; or c) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, the first cytokine receptor binding domain, VH1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in N-terminal to C-terminal order, VL1, and CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, VH2, CH12, and a second Fc domain subunit; a third polypeptide comprising, in N-terminal to C-terminal order, the second cytokine receptor binding domain, VL2, and CL2; wherein VH1, VL1, CH11, and CL1 form the first target binding domain, and VH2, VL2, CH12, and CL2 form the second target binding domain.

24. The pair of antigen binding molecules of any of the preceding claims, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, the first cytokine receptor binding domain, VH1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in N-terminal to C-terminal order, VL1, and CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, the second cytokine receptor binding domain, VH2, CH12, and a second Fc domain subunit; and a third polypeptide comprising, in N-terminal to C-terminal order, VL2, and CL2; or b) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, VH1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in N-terminal to C-terminal order, the first cytokine receptor binding domain, VL1, and CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, VH2, CH12, and a second Fc domain subunit; a third polypeptide comprising, in N-terminal to C-terminal order, the second cytokine receptor binding domain, VL2, and CL2; or c) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, the first cytokine receptor binding domain, VH1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, VL1, and CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH2, CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, the second cytokine receptor binding domain, VL2, and CL2; or d) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, the first cytokine receptor binding domain, VL1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, VH1, and CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, the second cytokine receptor binding domain, VH2, CH12, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, VL2, and CL2; or e) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VL1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in order from N-terminus to C-terminus, the first cytokine receptor binding domain, VH1, and CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH2, CH12, and a second Fc domain subunit; a third polypeptide comprising, in order from N-terminus to C-terminus, the second cytokine receptor binding domain, VL2, and CL2; or f) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, the first cytokine receptor binding domain, VL1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in N-terminal to C-terminal order, VH1, and CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, VH2, CH12, and a second Fc domain subunit; and a third polypeptide comprising, in N-terminal to C-terminal order, the second cytokine receptor binding domain, VL2, and CL2; or g) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, VL1, CH11, and a second Fc domain subunit; and a third polypeptide comprising, in N-terminal to C-terminal order, a first cytokine receptor binding domain, VH1, and CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, a second cytokine receptor binding domain, VH2, CH12, and a second Fc domain subunit; and a third polypeptide comprising, in N-terminal to C-terminal order, VL2, and CL2; wherein VH1, VL1, CH11, and CL1 form the first target binding domain, and VH2, VL2, CH12, and CL2 form the second target binding domain.

25. The pair of antigen binding molecules according to any of the preceding claims, wherein the first and second target binding domains bind specifically to FAP, and the first and second cytokine receptor subunits are subunits of the IFNy receptor complex.

26. The pair of antigen binding molecules according to any of the preceding claims, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 27; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 30; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 38; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 37; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 31; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 33; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 35; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 36; or e) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 27; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 33; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 30; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 31 ; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 38; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 36; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 37; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

35.

27. The pair of antigen-binding molecules of any one of claims 1-24, wherein the first and second target binding domains specifically bind to EGFR and the first and second cytokine receptor subunits are subunits of the IFNy receptor complex.

28. The pair of antigen-binding molecules of any one of claims 1-24 or 27, wherein a) the first antigen-binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 260; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen-binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 259; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127; or b) the first antigen-binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 256; and the second antigen-binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 122; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 255; or c) the first antigen-binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 261; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen-binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 258; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127; or d) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 257; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 254; or e) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 260, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 255; or f) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 256; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 259, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 127; or g) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 261, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 254; or h) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 119, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 257; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 258, and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

127.

29. The pair of antigen binding molecules of any one of claims 1 to 24, wherein the first target binding domain and the second target binding domain specifically bind to PD-1, and the first cytokine receptor subunit and the second cytokine receptor subunit are subunits of the IL-2 receptor complex.

30. The pair of antigen binding molecules of any one of claims 1 to 24 or 29, wherein a) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 86, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 83; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 87; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 92; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 91; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 95; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 101; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 99; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 102; or e) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 97; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 103; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 97; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 103; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

89. f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 100; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 104; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 99; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 101 ; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 95; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 102; or i) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 100; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 98; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 103; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or j) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 96; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 97; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 88; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

104.

31. The pair of antigen binding molecules of any one of claims 1-24, wherein the first target binding domain and the second target binding domain specifically bind to LAG-3 and the first cytokine receptor subunit and the second cytokine receptor subunit are subunits of the IL-2 receptor complex.

32. The pair of antigen binding molecules of any one of claims 1-24 or 31, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or c) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156, and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or d) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 162, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160, and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 157; or e) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160, and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or f) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160, and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158, and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

157. f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 162; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

157.

33. The pair of antigen binding molecules of any one of claims 1 to 24, wherein the first target binding domain and the second target binding domain specifically bind to EGFR and the first cytokine receptor subunit and the second cytokine receptor subunit are subunits of the IL-2 receptor complex.

34. The pair of antigen binding molecules of any one of claims 1 to 24 or 33, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or e) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

163. d) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 162, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160, and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 157; or e) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 161, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160, and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 165, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or f) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 154, and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or g) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 162, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 160; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 164, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 163; or h) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 155, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 156; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 158, and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

157.

35. The pair of antigen binding molecules of any one of claims 1 to 24, wherein the first target binding domain and the second target binding domain specifically bind to FAP and the first cytokine receptor subunit and the second cytokine receptor subunit are subunits of the IL-2 receptor complex.

36. The pair of antigen binding molecules of any one of claims 1 to 24 or 35, wherein a) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 110, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 113, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or b) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 105; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 109; or c) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 111, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or d) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 107; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 108; or e) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 110, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 109; or f) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 105; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 113, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or g) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 111, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 108; or h) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 107; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 112, and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

29.

37. The pair of antigen binding molecules of any one of claims 1 to 24, wherein the first target binding domain and the second target binding domain specifically bind to Her2, and the first cytokine receptor subunit and the second cytokine receptor subunit are subunits of the IL-2 receptor complex.

38. The pair of antigen binding molecules of any one of claims 1 to 24 or 37, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 136; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 134; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 138; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 137; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 135; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 134; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 138; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

139.

39. The pair of antigen binding molecules of any one of claims 1-24, wherein the first target binding domain and the second target binding domain specifically bind to Her3 and the first cytokine receptor subunit and the second cytokine receptor subunit are subunits of the IL-2 receptor complex.

40. The pair of antigen binding molecules of any one of claims 1-24 or 39, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 146; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 144; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 148; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 147; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 146; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 144; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 148; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

147. b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 145; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 144; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 148; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

149.

41. The pair of antigen binding molecules according to any one of claims 1 to 24, wherein the first target binding domain and the second target binding domain specifically bind to PD-1 and the first cytokine receptor subunit and the second cytokine receptor subunit are subunits of the IL-7 receptor complex.

42. The pair of antigen binding molecules according to any one of claims 1 to 24 and 41, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 194; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 193; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 195; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 196; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 197; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 198; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or e) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 199; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 200; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 201; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 202; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or i) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 203; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or j) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 204, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89; or k) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 106, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 205, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 124; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 90, and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

89.

43. The pair of antigen binding molecules of any one of claims 1-21, wherein the first target binding domain is fused at its C-terminus of CH11 to the N-terminus of the first Fc domain subunit and the first cytokine receptor binding domain is fused at its C-terminus to the N-terminus of the second Fc domain subunit and the second target binding domain is fused at its C-terminus of CH12 to the N-terminus of the first Fc domain subunit and the second cytokine receptor binding domain is fused at its C-terminus to the N-terminus of the second Fc domain subunit.

44. The pair of antigen binding molecules of any one of claims 1-21 or 43, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising, in order from N- terminus to C-terminus, VH1, CH11, and a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VL1, and CL1; and a third polypeptide comprising, in order from N-terminus to C-terminus, the first cytokine receptor binding domain and a second Fc domain subunit; and the second antigen binding molecule comprises: a first polypeptide comprising, in order from N- terminus to C-terminus, VH2, CH12, and a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VL2, and CL2; and a third polypeptide comprising, in order from N-terminus to C-terminus, the second cytokine receptor binding domain and a second Fc domain subunit; or b) the first antigen binding molecule comprises: a first polypeptide comprising, in order from N- terminus to C-terminus, VL1, CH11, and a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH1, and CL1; and a third polypeptide comprising, in order from N-terminus to C-terminus, the first cytokine receptor binding domain and a second Fc domain subunit; and the second antigen binding molecule comprises: a first polypeptide comprising, in order from N- terminus to C-terminus, VH2, CH12, and a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VL2, and CL2; and a third polypeptide comprising, in order from N-terminus to C-terminus, the second cytokine receptor binding domain and a second Fc domain subunit; wherein VH1, VL1, CH11, and CL1 form the first target binding domain, and VH2, VL2, CH12, and CL2 form the second target binding domain.

45. The pair of antigen binding molecules of any one of claims 1 to 21 or 43 to 44, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 32; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 39; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 34; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 40; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 34; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 39; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 32; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 40; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 237; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 238; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 235; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 236; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or e) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 239, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 240, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or f) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 235, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 237, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or g) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 236, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 235, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or h) the first antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 240, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 32, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 239, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 34, and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

29.

46. The pair of antigen-binding molecules of any one of claims 1-21, wherein the first target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits and the first cytokine receptor binding domain is fused at its N-terminus to the C-terminus of the same Fc domain subunit, and the second target binding domain is fused at its C-terminus to the N-terminus of one of the Fc domain subunits and the second cytokine receptor binding domain is fused at its N-terminus to the C-terminus of the same Fc domain subunit.

47. The pair of antigen-binding molecules of any one of claims 1-21 or 46, wherein a) the first antigen-binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH1, CH11, a second Fc domain subunit, and the first cytokine receptor binding domain; and a third polypeptide comprising, in order from N-terminus to C-terminus, VL1, and CL1; and the second antigen-binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH2, CH12, a second Fc domain subunit, and the second cytokine receptor binding domain; and a third polypeptide comprising, in order from N-terminus to C-terminus, VL2, and CL2; or b) the first antigen-binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VL1, CH11, a second Fc domain subunit, and the first cytokine receptor binding domain; and a third polypeptide comprising, in order from N-terminus to C-terminus, VH1, and CL1; and the second antigen-binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in order from N-terminus to C-terminus, VH2, CH12, a second Fc domain subunit, and the second cytokine receptor binding domain; and a third polypeptide comprising, in order from N-terminus to C-terminus, VL2, and CL2; or c) the first antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, VL1, CH11, a second Fc domain subunit, and the first cytokine receptor binding domain; and a third polypeptide comprising, in N-terminal to C-terminal order, VH1, and CL1; and the second antigen binding molecule comprises: a first polypeptide comprising a first Fc domain subunit; a second polypeptide comprising, in N-terminal to C-terminal order, VH2, CH12, a second Fc domain subunit, and the second cytokine receptor binding domain; and a third polypeptide comprising, in N-terminal to C-terminal order, VL2, and CL2; wherein VH1, VL1, CH11, and CL1 form the first target binding domain, and VH2, VL2, CH12, and CL2 form the second target binding domain.

48. The pair of antigen binding molecules of any one of claims 1 to 21 or 46 to 47, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 42; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 41; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 45; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 43; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 46; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 41; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 47; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 43; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 46; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 41; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 47; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 43; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 46; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 41; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 45; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 44; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

43. c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 246, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 249, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 242, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 245, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or e) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 250, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 253, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or f) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 248, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 247, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or g) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 244; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 243; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or h) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 252; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 25; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 251; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 29; or i) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 42; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 42; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 241; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 245; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

29.

49. The pair of antigen binding molecules according to any one of claims 1 to 11, wherein the first cytokine receptor binding domain and the second cytokine receptor binding domain are Fab molecules.

50. The pair of antigen binding molecules according to claim 49, wherein a) the first cytokine receptor binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 282 and a VL domain comprising the amino acid sequence of SEQ ID NO: 283, or the first cytokine receptor binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 284 and a VL domain comprising the amino acid sequence of SEQ ID NO: 285; and the second cytokine receptor domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 286 and a VL domain comprising the amino acid sequence of SEQ ID NO: 287, or the second cytokine receptor domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 288 and a VL domain comprising the amino acid sequence of SEQ ID NO: 289; or b) the first cytokine receptor binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 286 and a VL domain comprising the amino acid sequence of SEQ ID NO: 287, or the first cytokine receptor binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 288 and a VL domain comprising the amino acid sequence of SEQ ID NO: 289; and the second cytokine receptor domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 282 and a VL domain comprising the amino acid sequence of SEQ ID NO: 283, or the second cytokine receptor domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 284 and a VL domain comprising the amino acid sequence of SEQ ID NO: 285.

16.

51. The pair of antigen binding molecules of any one of claims 1 to 11, wherein the first cytokine receptor binding domain and the second cytokine receptor binding domain are scFv molecules.

52. The pair of antigen binding molecules of claim 51, wherein a) the first cytokine receptor binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 290 and a VL domain comprising the amino acid sequence of SEQ ID NO: 291; and the second cytokine receptor domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 292 and a VL domain comprising the amino acid sequence of SEQ ID NO: 293; or b) the first cytokine receptor binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 292 and a VL domain comprising the amino acid sequence of SEQ ID NO: 293, or the first cytokine receptor binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 290 and a VL domain comprising the amino acid sequence of SEQ ID NO: 291; and the second cytokine receptor domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 286 and a VL domain comprising the amino acid sequence of SEQ ID NO: 287, or the second cytokine receptor domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 288 and a VL domain comprising the amino acid sequence of SEQ ID NO:

289. b) the first cytokine receptor binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 292 and a VL domain comprising the amino acid sequence of SEQ ID NO: 293; and the second cytokine receptor domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 290 and a VL domain comprising the amino acid sequence of SEQ ID NO:

291.

53. The pair of antigen binding molecules of any one of claims 49 to 52, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule comprises a first Fc domain subunit and a second Fc domain subunit.

54. The pair of antigen binding molecules of any one of claims 49 to 53, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule is an IgG Fc domain, particularly an IgGl Fc domain.

55. The pair of antigen binding molecules of any one of claims 49 to 54, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule is a human Fc domain.

56. The pair of antigen binding molecules of any one of claims 49 to 55, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule comprises a modification that promotes association of the first and second subunits of the Fc domain.

57. The pair of antigen binding molecules of any one of claims 49 to 56, wherein the Fc domain of the first antigen binding molecule and the second antigen binding molecule comprises one or more amino acid substitution that reduces binding to an Fc receptor and / or effector function.

58. The pair of antigen binding molecules of any one of claims 49 to 57, wherein the cytokine receptor binding domain are fused to their respective fusion point via a peptide linker.

59. The pair of antigen binding molecules of claim 58, wherein the peptide linker comprises the amino acid sequence of SEQ ID NO: 280 or SEQ ID NO:

281.

60. The pair of antigen binding molecules of claim 49, wherein a) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 267; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 265; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 266; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 272; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 271; or b) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 267; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 265; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 266; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 274; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 273; or c) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 269; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 265; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 268; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 268; a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28; a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270; and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 271; or d) the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 269, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 265, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 268; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 274, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 270, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO:

273.

61. The pair of antigen binding molecules of claim 51, wherein the first antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 276, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 275; and the second antigen binding molecule comprises: a first polypeptide comprising the amino acid sequence of SEQ ID NO: 277, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 28, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 278.

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