Fibroblast targeting molecules

Abstract

Antigen-binding proteins that target cancer-associated fibroblasts are provided herein. Methods of treatment comprising administering a pharmaceutical composition comprising an antigen-binding protein as described herein are further provided.

Description

[0001] FIBROBLAST TARGETING MOLECULES CROSS-REFERENCE TO RELATED APPLICATIONS [1] This application claims the benefit of U.S. Provisional Patent Application No.63 / 596,210, filed November 3, 2023, which is hereby incorporated by reference in its entirety. INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY [2] Incorporated by reference in its entirety is a computer-readable nucleotide / amino acid sequence listing submitted concurrently herewith and identified as follows: 466 byte XML file named "FIBROBLAST TARGETING MOLECULES Sequence Listing"; created on November 3, 2023. FIELD OF THE INVENTION [3] The present invention relates to antigen-binding proteins that target cancer-associated fibroblasts (CAFs) for the treatment of cancer. BACKGROUND [4] The Fibroblast-activation protein ^ (FAP or FAP ^), also known as Seprase, is a type II integral membrane serine peptidase. FAP belongs to the dipeptidyl peptidase IV family (Yu et al., FEBS J. 277, 1126-1144 (2010)). It is a 170 KDa homodimer containing two N-glycosylated subunits with a large C-terminal extracellular domain, in which the enzyme’s catalytic domain is located (Scanlan et al., Proc Natl Acad Sci USA 91: 5657-5661 (1994); Wonganu et al., Biochim Biophys Acta 1858(8):1876-82 (2016)). FAP, in its glycosylated form, has both post-prolyl dipeptidyl peptidase and gelatinase activities (Sun et al., Protein Expr Purif 24, 274-281 (2002)). Homologues of human FAP were found in several species, including mice and cynomolgus monkeys (Macaca fascicularis). [5] FAP is expressed selectively in reactive stromal fibroblasts of more than 90% of epithelial malignancies (primary and metastatic) examined, including lung, colorectal, bladder, ovarian and breast carcinomas, and in malignant mesenchymal cells of bone and soft tissue sarcomas, while it is generally absent from normal adult tissues (Brennen et al., Mol. Cancer Ther.11(2): 257–266 (2012); Garin-Chesa et al., Proc Natl Acad Sci USA 87, 7235-7239 (1990); Rettig et al., Cancer Res. 53:3327–3335 (1993); Rettig et al., Proc Natl Acad Sci USA 85, 3110-3114 (1988)). FAP is also expressed on certain malignant tumor cells. Due to its expression in many common cancers and its restricted expression in normal tissues, FAP has been considered a promising antigenic target for imaging, diagnosis and therapy of a variety of cancers. [6] Various approaches have been devised to exploit the selective expression of FAP in tumor stroma for clinical benefit, including monoclonal antibodies against FAP and small-molecule inhibitors of FAP enzymatic activity. For example, Sibrotuzumab, a humanized antibody derived from F19 mouse antibody has been investigated for treatment of metastatic colorectal cancer and non-small cell lung cancer (Scott et al., Clin. Cancer Res.9, 1639–1647 (2003)). Some of the FAP targeting molecules have been reported to inhibit the enzymatic activity of FAP. For example, the scFv E3 inhibits FAP enzymatic activity and biological function (Zhang et al., FASEB J.2013 Feb; 27(2): 581– 589). However, the role of FAP in tumor biology is complex and not fully understood, and hence the potential effects of FAP inhibition in tumor biology are also not fully understood. [7] FAP expression in the tumor stroma has also led to attempts to develop locally activated prodrugs. Brennen et al. (Mol. Cancer Ther.11(2): 257–266 (2012)) discussed an approach of taking advantage of FAP’s restricted expression and unique substrate preferences to develop a FAP- activated prodrug to target the activation of a cytotoxic compound within the tumor stroma. [8] For molecules that can potentially cause systemic toxicity, such as certain T-cell co-stimulatory molecules, FAP can be used as a “localization” target, such that the activities of such anti-tumor molecules can be limited within tumor local environment. Therefore, there is a need to develop an FAP targeting molecule that can serve as a targeting moiety and selectively deliver cancer treatment agents to cancer tissues. SUMMARY [9] Based on the disclosure provided herein, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following embodiments (E).

[0010] The use of section headings herein is merely for the convenience of reading, and not intended to be limiting per se. The entire document is intended to be viewed as a unified disclosure, and it should be understood that all combinations of features described herein are contemplated. E1. A Fibroblast-activation protein ^ (FAP) antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said protein binds to an epitope that comprises residues V275, R175, F181, Q182, I183, D178, F185, P179, and Y274, according to the numbering of SEQ ID NO:394. E2. The FAP antigen-binding protein of E1, wherein said epitope further comprises one or more residues selected from the group consisting of: Q174, W327, P277, and Q278, according to the numbering of SEQ ID NO:394. E3. The FAP antigen-binding protein of E1 or E2, wherein said epitope further comprises residues Q174, W327, P277, and Q278, according to the numbering of SEQ ID NO:394. E4. The FAP antigen-binding protein of any one of E1-E3, wherein said epitope further comprises one or more residues selected from the group consisting of: P272, P180, I267, G276, D326, and A273, according to the numbering of SEQ ID NO:394. E5. The FAP antigen-binding protein of any one of E1-E3, wherein said epitope further comprises: P272, P180, I267, G276, D326, and A273, according to the numbering of SEQ ID NO:394. E6. The FAP antigen-binding protein of any one of E1-E4, wherein one or more of the following substitutions substantially disrupts the binding of said antigen-binding protein to said epitope: (1) R175 is replaced with A, N, D, C, Q, E, G, I, L, M, F, P, S, T. W, T, or V; (2) D178 is replaced with R, K, A, N, C, Q, G, I, L, M, F, P, S, T, W, Y, or V; (3) P179 is replaced with R, K, N, Q, I, M, F, W, Y, D, E, or H; (4) F181 is replaced with R, K, A, N, C, D, E, Q, G, I, L, M, P, S, T, V, or H; (5) F185 is replaced with R, K, A, N, C, D, E, Q, G, I, L, M, P, S, T, V or H; (6) Y274 is replaced with R, K, A, G, I, L, M, P, S, T, V, H, F, or W; or (7) V275 is replaced with R, K, N, Q, I, L, M, H, F, W, Y, D, or E. E7. The FAP antigen-binding protein of E6, wherein one or more of the following substitutions substantially disrupts the binding of said protein to said epitope: (8) Q174 is replaced with A, C, G, I, L, M, F, P, W, Y, or V; (9) P277 is replaced with R, K, N, Q, I, L, M, H, F, W, Y, D, or E; or (10) Q278 is replaced with A, R, K, I, L, M, F, W, or Y. E8. The FAP antigen-binding protein of E6 or E7, wherein one or more of the following substitutions substantially disrupts the binding of said protein to said epitope: (11) A273 is replaced with R, K, N, Q, I, M, F, W, Y, D, E, or H; or (12) G276 is replaced R, K, N, Q, I, L. M, H, F, W, Y, D, or E. E9. The FAP antigen-binding protein of any one of E1-E8, wherein said antigen-binding protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800-fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising one or more of the following substitutions: (1) R175 is replaced with A, N, D, C, Q, E, G, I, L, M, F, P, S, T. W, T, or V; (2) D178 is replaced with R, K, A, N, C, Q, G, I, L, M, F, P, S, T, W, Y, or V; (3) P179 is replaced with R, K, N, Q, I, M, F, W, Y, D, E, or H; (4) F181 is replaced with R, K, A, N, C, D, E, Q, G, I, L, M, P, S, T, V, or H; (5) F185 is replaced with R, K, A, N, C, D, E, Q, G, I, L, M, P, S, T, V or H; (6) Y274 is replaced with R, K, A, G, I, L, M, P, S, T, V, H, F, or W; or (7) V275 is replaced with R, K, N, Q, I, L, M, H, F, W, Y, D, or E. E10. The FAP antigen-binding protein of E9, wherein said protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800-fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising one or more of the following substitutions: (8) Q174 is replaced with A, C, G, I, L, M, F, P, W, Y, or V; (9) P277 is replaced with R, K, N, Q, I, L, M, H, F, W, Y, D, or E; or (10) Q278 is replaced with A, R, K, I, L, M, F, W, or Y. E11. The FAP antigen-binding protein of E9 or E10, wherein said protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800- fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising one or more of the following substitutions: (11) A273 is replaced with R, K, N, Q, I, M, F, W, Y, D, E, or H; or (12) G276 is replaced R, K, N, Q, I, L. M, H, F, W, Y, D, or E. E12. The FAP antigen-binding protein of any one of E9-E11, wherein said KD value is measured by surface plasmon resonance (SPR), optionally using a Biacore T200 instrument. E13. The FAP antigen-binding protein of any one of E9-E11, wherein said KD value is measured by bio-layer interferometry (BLI), optionally using a ForteBio Octet instrument. E14. The FAP antigen-binding protein of any one of E1-E13, wherein said FAP is a human FAP. E15. The FAP antigen-binding protein of E14, wherein said FAP comprises SEQ ID NO:395. E16. The FAP antigen-binding protein of any one of E1-E15, wherein said epitope is determined by X-ray crystallography or cryoEM. E17. The FAP antigen-binding protein of any one of E1-E16, wherein said VH and VL comprise (VH and VL numberings according to Kabat): (1) H33 is Arg, Lys, Gln, or Asn; (2) H94 is; Arg, Lys, Gln, or Asn; (3) H97 is Gly or Ala; (4) H98 is Tyr, Trp, Phe, Thr, or Ser; (5) H100B is Tyr, Trp, Phe, Thr, or Ser, (6) H100C is Tyr, Trp, Phe, Thr, or Ser; (7) L53 is Gln, Asn, or Glu; (8) L54 is Arg, Lys, Gln, or Asn; and (9) L60 is Asp, Glu, or Asn. E18. The FAP antigen-binding protein of any one of E1-E17, wherein said VH and VL comprise (VH and VL numberings according to Kabat): (1) H33 is Arg or Lys; (2) H94 is Arg or Lys; (3) H97 is Gly or Ala; (4) H98 is Tyr or Phe; (5) H100B is Tyr or Phe; (6) H100C is Tyr or Phe; (7) L53 is Gln or Asn; (8) L54 is Arg or Lys; and (9) L60 is Asp or Glu. E19. The FAP antigen-binding protein of any one of E1-E18, wherein said VH and VL comprise (VH and VL numberings according to Kabat): (1) H33 is Arg; (2) H94 is Arg; (3) H97 is Gly; (4) H98 is Tyr; (5) H100B is Tyr; (6) H100C is Tyr; (7) L53 is Gln; (8) L54 is Arg; and (9) L60 is Asp. E20. The FAP antigen-binding protein of any one of E17-E19, wherein said VH and VL further comprise (VH and VL numberings according to Kabat): (10) H31 is Asn, Gln, His, Asp, Lys, or Arg; (11) H34 is Val, Ile, Leu, Met, Phe, Ala, or Norleucine; (12) L49 is Tyr, Trp, Phe, Thr, or Ser; and (13) L50 is Ser or Thr. E21. The FAP antigen-binding protein of any one of E17-E20, wherein said VH and VL further comprise (VH and VL numberings according to Kabat): (10) H31 is Asn or Gln; (11) H34 is Val or Leu; (12) L49 is Tyr or Phe; and (13) L50 is Ser or Thr. E22. The FAP antigen-binding protein of any one of E17-E21, wherein said VH and VL further comprise (VH and VL numberings according to Kabat): (10) H31 is Asn; (11) H34 is Val; (12) L49 is Tyr; and (13) L50 is Ser. E23. The FAP antigen-binding protein of any one of E17-E19, wherein said VH and VL further comprise (VH and VL numberings according to Kabat): (14) H27 is Phe, Leu, Val, Ile, Ala, or Tyr; (15) H28 is Ser or Thr; (16) H30 is Ser or Thr, (17) H95 is Ile, Leu, Val, Met, Ala, Phe, or Norleucine; (18) H96 is Gly or Ala; (19) H101 is Asp, Glu, or Asn; and (20) L52 is Asn, Gln, His, Asp, Lys, or Arg. E24. The FAP antigen-binding protein of any one of E17-E20, wherein said VH and VL further comprise (VH and VL numberings according to Kabat): (14) H27 is Phe or Tyr; (15) H28 is Ser or Thr; (16) H30 is Ser or Thr, (17) H95 is Ile or Leu; (18) H96 is Gly or Ala; (19) H101 is Asp or Glu; and (20) L52 is Asn or Gln. E25. The FAP antigen-binding protein of any one of E17-E21, wherein said VH and VL further comprise (VH and VL numberings according to Kabat): (14) H27 is Phe; (15) H28 is Ser; (16) H30 is Ser, (17) H95 is Ile; (18) H96 is Gly; (19) H101 is Asp; and (20) L52 is Asn. E26. The FAP antigen-binding protein of any one of E1-E24, wherein: (a) said VH comprises: (i) a complementarity determining region (CDR)-H1 comprising any one of SEQ ID NOs: 398-402; and (ii) a CDR-H3 comprising any one of SEQ ID NOs: 408- 412; (b) said VL comprises a CDR-L2 comprising any one of SEQ ID NOs: 418-422; and (c) said VL further comprises a D at position L60 (numbering according to Kabat). E27. The FAP antigen-binding protein of E26, wherein said CDR-H1, CDR-H3, CDR-L2, and residue D at L60 contact one or more of FAP residues selected from the group consisting of: Q174, R175, D178, P179, P180, F181, Q182, I183, F185, I267, P272, A273, Y274, V275, G276, P277, Q278, D326, and W327 (numbering according to SEQ ID NO:394). E28. The FAP antigen-binding protein of E27, wherein said contacting is defined as within 4.5Å distance between a heavy atom in FAP and a heavy atom in the FAP antigen-binding protein, as determined by X-ray crystallography or cyroEM. E29. A Fibroblast-activation protein ^ (FAP) antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said protein binds to an epitope that comprises E325, D331, Q336, I320, R324, E302, R303, and T335, according to the numbering of SEQ ID NO:394. E30. The FAP antigen-binding protein of E29, wherein said epitope further comprises one or more residues selected from the group consisting of: K381, D322, P333, and F357, according to the numbering of SEQ ID NO:394. E31. The FAP antigen-binding protein of E29 or E30, wherein said epitope further comprises residues K381, D322, P333, and F357, according to the numbering of SEQ ID NO:394. E32. The FAP antigen-binding protein of any one of E20-E31, wherein said epitope further comprises one or more residues selected from the group consisting of: K219, D326, W327, A361, I362, S363, Y364, I380, D382, F323, and H338, according to the numbering of SEQ ID NO:394. E33. The FAP antigen-binding protein of any one of E29-E32, wherein said epitope further comprises residues K219, D326, W327, A361, I362, S363, Y364, I380, D382, F323, and H338, according to the numbering of SEQ ID NO:394. E34. The FAP antigen-binding protein of any one of E29-E33, wherein one or more of the following substitutions substantially disrupts the binding of said protein to said epitope: (1) E302 is replaced with A; (2) R303 is replaced with A; (3) I320 is replaced with A; (4) R324 is replaced with A; (5) E325 is replaced with A; (6) D331 is replaced with A; (7) T335 is replaced with A; or (8) Q336 is replaced with A. E35. The FAP antigen-binding protein of E34, wherein one or more of the following substitutions substantially disrupts the binding of said protein to said epitope: (9) D322 is replaced with A; or (10) P333 is replaced with W, R, K, F, H, I, M, or Y; F357 is replaced with A. E36. The FAP antigen-binding protein of E34 or E35, wherein one or more of the following substitutions substantially disrupts the binding of said protein to said epitope: (11) Y364 is replaced with A; or (12) D382 is replaced with W, R, K, F, H, I, M, or Y. E37. The FAP antigen-binding protein of any one of E29-E36, wherein said antigen-binding protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800-fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising one or more of the following substitutions: (1) E302 is replaced with A; (2) R303 is replaced with A; (3) I320 is replaced with A; (4) R324 is replaced with A; (5) E325 is replaced with A; (6) D331 is replaced with A; (7) T335 is replaced with A; or (8) Q336 is replaced with A. E38. The FAP antigen-binding protein of E37, wherein said antigen-binding protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800-fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising one or more of the following substitutions: (9) D322 is replaced with A; or (10) P333 is replaced with W, R, K, F, H, I, M, or Y; F357 is replaced with A. E39. The FAP antigen-binding protein of E37 or E38, wherein said antigen-binding protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800-fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising one or more of the following substitutions: (11) Y364 is replaced with A; or (12) D382 is replaced with W, R, K, F, H, I, M, or Y. E40. The FAP antigen-binding protein of any one of E37-E39, wherein said KD value is measured by surface plasmon resonance (SPR), optionally using a Biacore T200 instrument. E41. The FAP antigen-binding protein of any one of E37-E39, wherein said KD value is measured by bio-layer interferometry (BLI), optionally using a ForteBio Octet instrument. E42. The FAP antigen-binding protein of any one of E29-E41, wherein said FAP is a human FAP. E43. The FAP antigen-binding protein of E42, wherein said FAP comprises SEQ ID NO:395. E44. The FAP antigen-binding protein of any one of E29-E43, wherein said epitope is determined by X-ray crystallography or cryoEM. E45. The FAP antigen-binding protein of any one of E29-E44, wherein said VH comprises (VH numbering according to Kabat): (1) H31 is Arg, Lys, Gln, or Asn; (2) H98 is Tyr, Trp, Phe, Thr, or Ser; (3) H99 is Tyr, Trp, Phe, Thr, or Ser; (4) H100 is Tyr, Trp, Phe, Thr, or Ser; and (5) H101 is Asp, Glu, or Asn. E46. The FAP antigen-binding protein of any one of E29-E45, wherein said VH comprises (VH numbering according to Kabat): (1) H31 is Arg or Lys; (2) H98 is Tyr or Phe; (3) H99 is Tyr or Phe; (4) H100 is Tyr or Phe; and (5) H101 is Asp or Glu. E47. The FAP antigen-binding protein of any one of E29-E46, wherein said VH comprises (VH numbering according to Kabat): (1) H31 is Arg; (2) H98 is Tyr; (3) H99 is Tyr; (4) H100 is Tyr; and (5) H101 is Asp. E48. The FAP antigen-binding protein of any one of E45-E47, wherein said VH comprises (VH numbering according to Kabat): (6) H28 is Thr or Ser; and (7) H100A is Tyr, Trp, Phe, Thr, or Ser. E49. The FAP antigen-binding protein of any one of E45-E48, wherein said VH comprises (VH numbering according to Kabat): (6) H28 is Thr or Ser; and (7) H100A is Tyr or Phe. E50. The FAP antigen-binding protein of any one of E45-E49, wherein said VH comprises (VH numbering according to Kabat): (6) H28 is Thr; and (7) H100A is Tyr. E51. The FAP antigen-binding protein of any one of E45-E50, wherein said VH comprises (VH and VL numbering according to Kabat): (8) H32 is Tyr, Trp, Phe, Thr, or Ser; (9) H96 is Pro or Ala; (10) H97 is Ser or Thr; (11) H100C is Tyr, Trp, Phe, Thr, or Ser; (12) L32 is Phe, Leu, Val, Ile, Ala, or Tyr; and (13) L49 is Tyr, Trp, Phe, Thr, or Ser. E52. The FAP antigen-binding protein of any one of E45-E51, wherein said VH comprises (VH and VL numbering according to Kabat): (8) H32 is Tyr or Phe; (9) H96 is Pro or Ala; (10) H97 is Ser or Thr; (11) H100C is Tyr or Phe; (12) L32 is Phe or Tyr; and (13) L49 is Tyr or Phe. E53. The FAP antigen-binding protein of any one of E45-E52, wherein said VH comprises (VH and VL numbering according to Kabat): (8) H32 is Tyr; (9) H96 is Pro; (10) H97 is Ser; (11) H100C is Tyr; (12) L32 is Phe; and (13) L49 is Tyr. E54. The FAP antigen-binding protein of any one of E29-E53, wherein: (a) said VH comprises: (i) a complementarity determining region (CDR)-H1 comprising any one of SEQ ID NOs: 428-432; and (ii) a CDR-H3 comprising any one of SEQ ID NOs: 438- 442; and (b) said VL comprises a CDR-L2 comprising any one of SEQ ID NOs: 448-452. E55. The FAP antigen-binding protein of E54, wherein said CDR-H1, CDR-H3, and CDR-L2 contact one or more FAP residues selected from the group consisting of: K219, E302, R303, I320, D322, F323, R324, E325, D326, W327, D331, P333, T335, Q336, H338, F357, A361, I362, S363, Y364, I380, K381, and D382 (numbering according to SEQ ID NO:394). E56. The FAP antigen-binding protein of E55, wherein said contacting is defined as within 4.5Å distance between a heavy atom in FAP and a heavy atom in the FAP antigen-binding protein, as determined by X-ray crystallography or cyroEM. E57. A Fibroblast-activation protein ^ (FAP) antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said protein binds to an epitope that comprises S86, E82, I181, T83, Q85, Q65, K486, N80, T88, I485 and I487, according to the numbering of SEQ ID NO:394. E58. The FAP antigen-binding protein of E57, wherein said epitope further comprises one or more residues selected from the group consisting of: V77, G84, Y79, and Y87, according to the numbering of SEQ ID NO:394. E59. The FAP antigen-binding protein of E57 or E58, wherein said epitope further comprises residues V77, G84, Y79, and Y87, according to the numbering of SEQ ID NO:394. E60. The FAP antigen-binding protein of any one of E57-E59, wherein said epitope further comprises one or more residues selected from the group consisting of: E66, Y67, S71, D73, N75, S136, and L488, according to the numbering of SEQ ID NO:394. E61. The FAP antigen-binding protein of any one of E57-E60, wherein said epitope further comprises residues E66, Y67, S71, D73, N75, S136, and L488, according to the numbering of SEQ ID NO:394. E62. The FAP antigen-binding protein of any one of E57-E61, wherein one or more of the following substitutions substantially disrupts the binding of said protein to said epitope: (1) Q65 is replaced with A; (2) N80 is replaced with A; (3) E82 is replaced with A; (4) T83 is replaced with A; (5) Q85 is replaced with A; (6) S86 is replaced with A: (7) T88 is replaced with A; (8) I485 is replaced with A; or (9) K486 is replaced with A. E63. The FAP antigen-binding protein of E62, wherein one or more of the following substitutions substantially disrupts the binding of said protein to said epitope: (10) V77 is replaced with A; (11) Y79 is replaced with A; (12) G84 is replaced with A; or (13) Y87 is replaced with A. E64. The FAP antigen-binding protein of E62 or E63, wherein the following substitution substantially disrupts the binding of said protein to said epitope: (14) N75 is replaced with F, Y, or W. E65. The FAP antigen-binding protein of any one of E57-E64, wherein said antigen-binding protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800-fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising one or more of the following substitutions: (1) Q65 is replaced with A; (2) N80 is replaced with A; (3) E82 is replaced with A; (4) T83 is replaced with A; (5) Q85 is replaced with A; (6) S86 is replaced with A: (7) T88 is replaced with A; (8) I485 is replaced with A; or (9) K486 is replaced with A. E66. The FAP antigen-binding protein of E65, wherein said antigen-binding protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800-fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising one or more of the following substitutions: (10) V77 is replaced with A; (11) Y79 is replaced with A; (12) G84 is replaced with A; or (13) Y87 is replaced with A. E67. The FAP antigen-binding protein of E65 or E66, wherein said antigen-binding protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800-fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising the following substitution: (14) N75 is replaced with F, Y, or W. E68. The FAP antigen-binding protein of any one of E65-E67, wherein said KD value is measured by surface plasmon resonance (SPR), optionally using a Biacore T200 instrument. E69. The FAP antigen-binding protein of any one of E65-E67, wherein said KD value is measured by bio-layer interferometry (BLI), optionally using a ForteBio Octet instrument. E70. The FAP antigen-binding protein of any one of E57-E69, wherein said FAP is a human FAP. E71. The FAP antigen-binding protein of E70, wherein said FAP comprises SEQ ID NO:395. E72. The FAP antigen-binding protein of any one of E57-E71, wherein said epitope is determined by X-ray crystallography or cryoEM. E73. The FAP antigen-binding protein of any one of E57-E72, wherein said VH comprises (VH numbering according to Kabat): (1) H31 is Asn, Gln, His, Asp, Lys, or Arg; (2) H33 is Gly, or Ala; (3) H52A is Tyr, Trp, Phe, Thr, or Ser; (4) H55 is Arg, Lys, Gln, or Asn; (5) H56 is Asn, Gln, His, Asp, Lys, or Arg; (6) H95 is Asp, Glu, or Asn; (7) H100 is Gly or Ala; (8) L32 is Tyr, Trp, Phe, Thr, or Ser; (9) L91 is Phe, Leu, Val, Ile, Ala, or Tyr; and (10) L95 is Tyr, Trp, Phe, Thr, or Ser. E74. The FAP antigen-binding protein of any one of E57-E73, wherein said VH comprises (VH numbering according to Kabat): (1) H31 is Asn or Gln; (2) H33 is Gly, or Ala; (3) H52A is Tyr or Phe; (4) H55 is Arg or Lys; (5) H56 is Asn or Gln; (6) H95 is Asp or Glu; (7) H100 is Gly or Ala; (8) L32 is Tyr or Phe; (9) L91 is Phe or Tyr; and (10) L95 is Tyr or Phe. E75. The FAP antigen-binding protein of any one of E57-E74, wherein said VH comprises (VH numbering according to Kabat): (1) H31 is Asn; (2) H33 is Gly; (3) H52A is Tyr; (4) H55 is Arg; (5) H56 is Asn; (6) H95 is Asp; (7) H100 is Gly; (8) L32 is Tyr; (9) L91 is Phe; and (10) L95 is Tyr. E76. The FAP antigen-binding protein of any one of E73-E75, wherein said VH comprises (VH numbering according to Kabat): (11) H28 is Thr or Ser; (12) H32 is Tyr, Trp, Phe, Thr, or Ser; (13) H52 is Trp, Tyr, or Phe; (14) L30 is Tyr, Trp, Phe, Thr, or Ser; and (15) L96 is Trp, Tyr, or Phe. E77. The FAP antigen-binding protein of any one of E73-E76, wherein said VH comprises (VH numbering according to Kabat): (11) H28 is Thr or Ser; (12) H32 is Tyr or Phe; (13) H52 is Trp or Tyr; (14) L30 is Tyr or Phe; and (15) L96 is Trp or Tyr. E78. The FAP antigen-binding protein of any one of E73-E77, wherein said VH comprises (VH numbering according to Kabat): (11) H28 is Thr; (12) H32 is Tyr; (13) H52 is Trp; (14) L30 is Tyr; and (15) L96 is Trp. E79. The FAP antigen-binding protein of any one of E73-E78, wherein said VH comprises (VH and VL numbering according to Kabat): (16) H30 is Asn, Gln, His, Asp, Lys, or Arg; (17) H53 is Asp, Glu, or Asn; (18) H96 is Gly or Ala; (19) H97 is Ser or Thr; (20) H98 is Gly or Ala; (21) H99 is Gly or Ala; and (22) L56 is Ser or Thr. E80. The FAP antigen-binding protein of any one of E73-E79, wherein said VH comprises (VH and VL numbering according to Kabat): (16) H30 is Asn or Gln; (17) H53 is Asp or Glu; (18) H96 is Gly or Ala; (19) H97 is Ser or Thr; (20) H98 is Gly or Ala; (21) H99 is Gly or Ala; and (22) L56 is Ser or Thr. E81. The FAP antigen-binding protein of any one of E73-E80, wherein said VH comprises (VH and VL numbering according to Kabat): (16) H30 is Asn; (17) H53 is Asp; (18) H96 is Gly; (19) H97 is Ser; (20) H98 is Gly; (21) H99 is Gly; and (22) L56 is Ser. E82. The FAP antigen-binding protein of any one of E57-E81, wherein: (a) said VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 458-462; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 463-467; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 468-472; and (b) said VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 473-487; (ii) a CDR- L2 comprising any one of SEQ ID NOs: 478-482; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 483-487. E83. The FAP antigen-binding protein of E45, wherein said CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 contact one or more FAP residues selected from the group consisting of: Q65, N75, V77, Y79, N80, E82, T83, G84, Q85, S86, Y87, T88, I485, and K486 (numbering according to SEQ ID NO:394). E84. The FAP antigen-binding protein of E83, wherein said contacting is defined as within 4.5Å distance between a heavy atom in FAP and a heavy atom in the FAP antigen-binding protein, as determined by X-ray crystallography or cyroEM. E85. A Fibroblast-activation protein ^ (FAP) antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said protein binds to an epitope that comprises K381, K371, E414, S428, Q389, Y432, I390, P434, and K436, according to the numbering of SEQ ID NO:394. E86. The FAP antigen-binding protein of E85, wherein said epitope further comprises one or more residues selected from the group consisting of: I427, I388, G430, P433, and I426, according to the numbering of SEQ ID NO:394. E87. The FAP antigen-binding protein of E85 or E86, wherein said epitope further comprises residues I427, I388, G430, P433, and I426, according to the numbering of SEQ ID NO:394. E88. The FAP antigen-binding protein of any one of E85-E87, wherein said epitope further comprises one or more residues selected from the group consisting of: W395, S435, Y379, N386, A387, and S392, according to the numbering of SEQ ID NO:394. E89. The FAP antigen-binding protein of any one of E85-E88, wherein said epitope further comprises W395, S435, Y379, N386, A387, and S392, according to the numbering of SEQ ID NO:394. E90. The FAP antigen-binding protein of any one of E85-E89, wherein one or more of the following substitutions substantially disrupts the binding of said antigen-binding protein to said epitope: (1) K371 is replaced with A; (2) K381 is replaced with A; (3) E414 is replaced with A; (4) I390 is replaced with A; (5) Y432 is replaced with A; (6) P434 is replaced with F; or (7) K436 is replaced with A. E91. The FAP antigen-binding protein E90, wherein one or more of the following substitutions substantially disrupts the binding of said antigen-binding protein to said epitope: (8) I388 is replaced with A; (9) I427 is replaced with A; (10) G430 is replaced with A, or (11) P433 is replaced with F. E92. The FAP antigen-binding protein of any one of E85-E91, wherein said antigen-binding protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800-fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising one or more of the following substitutions: (1) K371 is replaced with A; (2) K381 is replaced with A; (3) E414 is replaced with A; (4) I390 is replaced with A; (5) Y432 is replaced with A; (6) P434 is replaced with F; or (7) K436 is replaced with A. E93. The FAP antigen-binding protein of E92, wherein said antigen-binding protein binds to said epitope with a binding affinity (KD) value that is at least 100-fold less, at least 200-fold less, at least 300-fold less, at least 400-fold less, at least 500-fold less, at least 600-fold less, at least 700-fold less, at least 800-fold less, at least 900-fold less, or at least 1000-fold less, than its KD value for an epitope comprising one or more of the following substitutions: (8) I388 is replaced with A; (9) I427 is replaced with A; (10) G430 is replaced with A, or (11) P433 is replaced with F. E94. The FAP antigen-binding protein of E92 or E93, wherein said KD value is measured by surface plasmon resonance (SPR), optionally using a Biacore T200 instrument. E95. The FAP antigen-binding protein of E92 or E93, wherein said KD value is measured by bio- layer interferometry (BLI), optionally using a ForteBio Octet instrument. E96. The FAP antigen-binding protein of any one of E85-E95, wherein said FAP is a human FAP. E97. The FAP antigen-binding protein of E96, wherein said FAP comprises SEQ ID NO:395. E98. The FAP antigen-binding protein of any one of E85-E97, wherein said epitope is determined by X-ray crystallography or cryoEM. E99. The FAP antigen-binding protein of any one of E85-E98, wherein said VH and VL comprise (VH and VL numbering according to Kabat): (1) H28 is Thr or Ser; (2) H53 is Asp, Glu, or Asn; (3) H96 is Arg, Lys, Gln, or Asn; (4) H99 is Tyr, Trp, Phe, Thr, or Ser; (5) H100A is Tyr, Trp, Phe, Thr, or Ser; (6) H100B is Tyr, Trp, Phe, Thr, or Ser; and (7) H100C is Tyr, Trp, Phe, Thr, or Ser. E100. The FAP antigen-binding protein of any one of E85-E99, wherein said VH and VL comprise (VH and VL numbering according to Kabat): (1) H28 is Thr or Ser; (2) H53 is Asp or Glu; (3) H96 is Arg or Lys; (4) H99 is Tyr or Phe; (5) H100A is Tyr or Phe; (6) H100B is Tyr or Phe; and (7) H100C is Tyr or Phe. E101. The FAP antigen-binding protein of any one of E85-E100, wherein said VH and VL comprise (VH and VL numbering according to Kabat): (1) H28 is Thr; (2) H53 is Asp; (3) H96 is Arg; (4) H99 is Tyr; (5) H100A is Tyr; (6) H100B is Tyr; and (7) H100C is Tyr. E102. The FAP antigen-binding protein of any one of E99-E101, wherein said VH and VL comprise (VH and VL numbering according to Kabat): (8) H31 is Ser or Thr; (9) H52 is Trp, Tyr, or Phe; (10) H97 is Leu, Norleucine, Ile, Val, Met, Ala, or Phe; (11) H98 is Gln, Asn, or Glu; (12) L32 is Leu, Norleucine, Ile, Val, Met, Ala, or Phe; (13) L91 is Tyr, Trp, Phe, Thr, or Ser; and (14) L96 is Trp, Tyr, or Phe. E103. The FAP antigen-binding protein of any one of E99-E102, wherein said VH and VL comprise (VH and VL numbering according to Kabat): (8) H31 is Ser or Thr; (9) H52 is Trp or Tyr; (10) H97 is Leu or Ile; (11) H98 is Gln or Asn; (12) L32 is Leu or Ile; (13) L91 is Tyr or Phe; and (14) L96 is Trp or Tyr. E104. The FAP antigen-binding protein of any one of E99-E103, wherein said VH and VL comprise (VH and VL numbering according to Kabat): (8) H31 is Ser; (9) H52 is Trp; (10) H97 is Leu; (11) H98 is Gln; (12) L32 is Leu; (13) L91 is Tyr; and (14) L96 is Trp. E105. The FAP antigen-binding protein of any one of E99-E104, wherein said VH and VL comprise (VH and VL numbering according to Kabat): (15) H30 is Ser or Thr; (16) H95 is Asp, Glu, or Asn; (17) H100 is Asp, Glu, or Asn; and (18) L30 is Tyr, Trp, Phe, Thr, or Ser. E106. The FAP antigen-binding protein of any one of E99-E105, wherein said VH and VL comprise (VH and VL numbering according to Kabat): (15) H30 is Ser or Thr; (16) H95 is Asp and Glu; (17) H100 is Asp or Glu; and (18) L30 is Tyr and Phe. E107. The FAP antigen-binding protein of any one of E99-E106, wherein said VH and VL comprise (VH and VL numbering according to Kabat): (15) H30 is Ser; (16) H95 is Asp; (17) H100 is Asp; and (18) L30 is Tyr. E108. The FAP antigen-binding protein of any one of E85-E107, wherein: (a) said VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 488-492; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 493-497; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 498-502; and (b) said VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 503-507; and (ii) a CDR-L3 comprising any one of SEQ ID NOs: 513-517. E109. The FAP antigen-binding protein of E108, wherein said CDR-H1, CDR-H2, CDR-H3, CDR-L2, and CDR-L3 contact one or more FAP residues selected from the group consisting of: K381, K371, E414, S428, Q389, Y432, I390, P434, K436, I427, I388, G430, P433, I429, W395, S435, Y379, N386, A387, and S392 (numbering according to SEQ ID NO:394). E110. The FAP antigen-binding protein of E109, wherein said contacting is defined as within 4.5Å distance between a heavy atom in FAP and a heavy atom in the FAP antigen-binding protein, as determined by X-ray crystallography or cyroEM. E111. A FAP antigen-binding protein comprising: (1) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 197, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 198; (2) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 199, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 200; (3) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 201, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 202; (4) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 203, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 204; (5) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 205, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 206; (6) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 207, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 208; (7) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 209, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 210; (8) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 211, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 212; (9) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 213, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 214; (10) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 215, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 216; (11) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 217, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 218; (12) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 219, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 220; (13) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 221, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 222; (14) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 223, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 224; (15) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 225, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 226; (16) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 227, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 228; (17) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 229, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 230; (18) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 231, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 232; (19) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 233, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 234; (20) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 235, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 236; (21) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 237, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 238; (22) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 239, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 240; (23) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 241, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 242; (24) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 243, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 244; (25) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 245, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 246; (26) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 247, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 248; (27) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 249, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 250; (28) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 251, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 252; (29) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 253, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 254; (30) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 255, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 256; (31) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 257, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 258; (32) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 259, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 260; (33) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 261, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 262; (34) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 263, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 264; (35) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 265, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 266; (36) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 267, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 268; (37) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 269, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 270; (38) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 271, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 272; (39) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 273, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 274; (40) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 275, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 276; (41) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 277, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 278; (42) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 279, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 280; (43) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 281, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 282; (44) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 283, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 284; (45) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 285, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 286; (46) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 287, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 288; (47) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 289, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 290; (48) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 291, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 292; (49) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 293, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 294; (50) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 295, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 296; (51) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 297, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 298; (52) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 299, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 300; (53) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 301, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 302; (54) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 303, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 304; (55) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 305, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 306; (56) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 307, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 308; (57) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 309, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 310; (58) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 311, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 312; (59) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 313, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 314; (60) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 315, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 316; (61) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 317, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 318; (62) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 319, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 320; (63) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 321, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 322; (64) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 323, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 324; (65) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 325, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 326; (66) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 327, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 328; (67) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 329, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 330; (68) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 331, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 332; (69) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 333, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 334; (70) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 335, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 336; (71) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 337, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 338; (72) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 339, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 340; or (73) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 341, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 342. E112. A FAP antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said VH and VL comprise: (i) a CDR-H1 comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 1, 7, 13, 19, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 121, 127, 133, 139, 145, 151, 157, 163, 169, 175, 181, 187, 398, 399, 400, 401, 402, 428, 429, 430, 431, 432, 458, 459, 460, 461, 462, 488, 489, 490, 491, or 492; (ii) a CDR-H2 comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 2, 8, 14, 20, 26, 32, 38, 44, 50, 56, 62, 68, 74, 80, 86, 92, 98, 104, 110, 116, 122, 128, 134, 140, 146, 152, 158, 164, 170, 176, 182, 188, 403, 404, 405, 406, 407, 433, 434, 435, 436, 437, 463, 464, 465, 466, 467, 493, 494, 495, 496, or 497; (iii) a CDR-H3 comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 3, 9, 15, 21, 27, 33, 39, 45, 51, 57, 63, 69, 75, 81, 87, 93, 99, 105, 111, 117, 123, 129, 135, 141, 147, 153, 159, 165, 171, 177, 183, 189, 194, 196, 408, 409, 410, 411, 412, 438, 439, 440, 441, 442, 468, 469, 470, 471, 472, 498, 499, 500, 501, or 502; (iv) a CDR-L1 comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 4, 10, 16, 22, 28, 34, 40, 46, 52, 58, 64, 70, 76, 82, 88, 94, 100, 106, 112, 118, 124, 130, 136, 142, 148, 154, 160, 166, 172, 178, 184, 190, 413, 414, 415, 416, 417, 443, 444, 445, 446, 447, 473, 474, 475, 476, 477, 503, 504, 505, 506, or 507; (v) a CDR-L2 comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 5, 11, 17, 23, 29, 35, 41, 47, 53, 59, 65, 71, 77, 83, 89, 95, 101, 107, 113, 119, 125, 131, 137, 143, 149, 155, 161, 167, 173, 179, 185, 191, 418, 419, 420, 421, 422, 448, 449, 450, 451, 452, 478, 479, 480, 481, 482, 508, 509, 510, 511, or 512; and (vi) a CDR-L3 comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 193, 195, 423, 424, 425, 426, 427, 453, 454, 455, 456, 457, 483, 484, 485, 486, 487, 513, 514, 515, 516, or 517. E113. The FAP antigen-binding protein of any one of E1-E112, comprising: (1) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.1-6, respectively; (2) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.6-12, respectively; (3) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.13-18, respectively; (4) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.19-24, respectively; (5) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.25-30, respectively; (6) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.31-36, respectively; (7) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.37-42, respectively; (8) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.43-48, respectively; (9) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.49-54, respectively; (10) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.55-60, respectively; (11) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.61-66, respectively; (12) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.67-72, respectively; (13) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.73-78, respectively; (14) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.79-84, respectively; (15) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.85-90, respectively; (16) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.91-96, respectively; (17) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.97-102, respectively; (18) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.103-108, respectively; (19) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.109-114, respectively; (20) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.115-120, respectively; (21) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.121-126, respectively (22) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.127-132, respectively; (23) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.133-138, respectively; (24) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.139-144, respectively; (25) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.145-150, respectively; (26) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.151-156, respectively; (27) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.157-162, respectively; (28) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.163-168, respectively; (29) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.169-174, respectively; (30) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.175-180, respectively; (31) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.181-186, respectively; (32) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.187-192, respectively; (33) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.43, 44, 45, 46, 47, and 193, respectively; (34) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.43, 44, 194, 46, 47, and 193, respectively; (35) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.175, 176, 177, 178, 179, and 195, respectively; or (36) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.187, 188, 196, 190, 191, and 192, respectively. E114. The FAP antigen-binding protein of any one of E1-E112, wherein: (a) said VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 398-402; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 403-407; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 408-412; and (b) said VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 413-417; (ii) a CDR- L2 comprising any one of SEQ ID NOs: 418-422; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 423-427. E115. The FAP antigen-binding protein of any one of E1-E112, wherein: (a) said VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 428-432; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 433-437; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 438-442; and (b) said VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 443-447; (ii) a CDR- L2 comprising any one of SEQ ID NOs: 448-452; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 453-457. E116. The FAP antigen-binding protein of any one of E1-E112, wherein: (a) said VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 458-462; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 463-467; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 468-472; and (b) said VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 473-477; (ii) a CDR- L2 comprising any one of SEQ ID NOs: 478-482; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 483-487. E117. The FAP antigen-binding protein of any one of E1-E112, wherein: (a) said VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 488-492; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 493-497; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 498-502; and (b) said VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 503-507; (ii) a CDR- L2 comprising any one of SEQ ID NOs: 508-512; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 513-517. E118. The FAP antigen-binding protein of any one of E1-E117, comprising a VL framework derived from a human germline V ^ framework sequence, such as a V ^1 framework sequence or a V ^2 framework sequence. E119. The FAP antigen-binding protein of any one of E1-E117, comprising a VL framework derived from a human germline V ^ framework sequence, such as a V ^1 framework sequence, a V ^2 framework sequence, or V ^3 framework sequence. E120. The FAP antigen-binding protein of any one of E1-E119, comprising a VH framework derived from a human germline VH1, VH2, VH3, VH4, or VH5 framework sequence. E121. The FAP antigen-binding protein of any one of E1-E120, comprising a VH framework derived from a human germline VH1 framework sequence. E122. The FAP antigen-binding protein of any one of E1-E120, comprising a VH framework derived from a human germline VH2 framework sequence. E123. The FAP antigen-binding protein of any one of E1-E120, comprising a VH framework derived from a human germline VH3 framework sequence. E124. The FAP antigen-binding protein of any one of E1-E120, comprising a VH framework derived from a human germline VH4 framework sequence. E125. The FAP antigen-binding protein of any one of E118-E124, comprising a VL framework sequence and a VH framework sequence, and wherein the VL framework sequence is at least 90% identical to the human germline framework sequence from which it is derived, and the VH framework sequence is at least 90% identical to the human germline framework sequence from which it is derived. E126. The FAP antigen-binding protein of any one of E118-E125, comprising a VL framework sequence and a VH framework sequence, and wherein the VL framework sequence is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the human germline framework sequence from which it is derived, and the VH framework sequence is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the human germline framework sequence from which it is derived. E127. The FAP antigen-binding protein of any one of E1-E126, comprising a heavy chain variable region (VH) that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, or 341. E128. The FAP antigen-binding protein of any one of E1-E127, comprising a light chain variable region (VL) that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, or 342. E129. The FAP antigen-binding protein of any one of E1-E128, comprising: (1) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 197, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 198; (2) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 199, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 200; (3) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 201, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 202; (4) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 203, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 204; (5) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 205, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 206; (6) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 207, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 208; (7) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 209, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 210; (8) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 211, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 212; (9) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 213, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 214; (10) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 215, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 216; (11) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 217, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 218; (12) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 219, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 220; (13) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 221, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 222; (14) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 223, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 224; (15) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 225, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 226; (16) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 227, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 228; (17) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 229, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 230; (18) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 231, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 232; (19) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 233, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 234; (20) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 235, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 236; (21) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 237, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 238; (22) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 239, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 240; (23) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 241, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 242; (24) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 243, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 244; (25) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 245, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 246; (26) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 247, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 248; (27) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 249, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 250; (28) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 251, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 252; (29) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 253, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 254; (30) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 255, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 256; (31) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 257, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 258; (32) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 259, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 260; (33) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 261, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 262; (34) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 263, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 264; (35) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 265, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 266; (36) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 267, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 268; (37) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 269, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 270; (38) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 271, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 272; (39) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 273, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 274; (40) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 275, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 276; (41) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 277, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 278; (42) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 279, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 280; (43) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 281, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 282; (44) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 283, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 284; (45) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 285, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 286; (46) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 287, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 288; (47) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 289, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 290; (48) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 291, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 292; (49) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 293, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 294; (50) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 295, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 296; (51) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 297, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 298; (52) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 299, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 300; (53) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 301, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 302; (54) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 303, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 304; (55) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 305, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 306; (56) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 307, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 308; (57) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 309, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 310; (58) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 311, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 312; (59) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 313, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 314; (60) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 315, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 316; (61) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 317, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 318; (62) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 319, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 320; (63) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 321, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 322; (64) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 323, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 324; (65) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 325, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 326; (66) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 327, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 328; (67) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 329, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 330; (68) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 331, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 332; (69) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 333, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 334; (70) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 335, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 336; (71) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 337, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 338; (72) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 339, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 340; or (73) a VH comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 341, and a VL comprising a sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 342. E130. The FAP antigen-binding protein of any one of E1-E129, further comprising a heavy chain CH1 domain. E131. The FAP antigen-binding protein of E130, wherein said CH1 domain is the CH1 domain of an IgG (for example IgG1, lgG2, lgG3, or lgG4). E132. The FAP antigen-binding protein of E130 or E131, wherein said CH1 domain is the CH1 domain of a human IgG (for example, human IgG1, human IgG2, human IgG3, or human IgG4). E133. The FAP antigen-binding protein of any one of E130-E132, wherein said CH1 domain comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:347, 364, 368, or 372. E134. The FAP antigen-binding protein of any one of E130-E133, wherein said CH1 domain comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:347. E135. The FAP antigen-binding protein of any one of E1-E134, further comprising an Fc region. E136. The FAP antigen-binding protein of E135, wherein the Fc region is the Fc region of an IgA (for example IgA1 or lgA2), IgD, IgE, IgM, or IgG (for example IgG1, lgG2, lgG3, or lgG4). E137. The FAP antigen-binding protein of E135 or E136, wherein the Fc region is the Fc region of an IgG. E138. The FAP antigen-binding protein of E137, wherein the IgG is selected from the group consisting of IgG1, lgG2, lgG3, and lgG4. E139. The FAP antigen-binding protein of E138, wherein the IgG is IgG1, IgG2, or IgG4. E140. The FAP antigen-binding protein of any one of E135-E139, wherein said Fc region is derived from an IgG Fc, and further comprises one or more mutations selection from the group consisting of: L234A, L235A, L235E, G237A, and combination thereof (numbering according to the EU index). E141. The FAP antigen-binding protein of E140, comprising L234A and L235A mutations. E142. The FAP antigen-binding protein of any one of E135-E141, wherein said Fc region is derived from an IgG Fc, and further comprises one or more mutations selection from the group consisting of: V259C, A287C, R292C, V302C, L306C, V323C, I332C, and a combination thereof (numbering according to the EU index). E143. The FAP antigen-binding protein of any one of E135-E142, wherein said Fc region is derived from an IgG Fc, and further comprises one or more mutations selection from the group consisting of: L242C, A287C, R292C, N297G, V302C, L306C, K334C, and a combination thereof (numbering according to the EU index). E144. The FAP antigen-binding protein of E143, comprising a N297G mutation. E145. The FAP antigen-binding protein of E143, comprising A287C, N297G, and L306C mutations. E146. The FAP antigen-binding protein of E143, comprising R292C, N297G, and V302C mutations. E147. The FAP antigen-binding protein of any one of E135-E146, wherein said Fc region is derived from an IgG Fc, and further comprises one or more mutations selection from the group consisting of: M252Y, S254T, T256E, and a combination thereof. E148. The FAP antigen-binding protein of E147, comprising M252Y, S254T, T256E mutations. E149. The FAP antigen-binding protein of any one of E135-E148, wherein the lysine residue (K) at the C-terminus of the Fc region is deleted. E150. The FAP antigen-binding protein of any one of E135-E148, wherein the lysine residue (K) at the C-terminus of the Fc region is present. E151. The FAP antigen-binding protein of any one of E135-E148, wherein the glycine and lysine residues (GK) at the C-terminus of the Fc region are present. E152. The FAP antigen-binding protein of any one of E135-E148, wherein the glycine and lysine residues (GK) at the C-terminus of the Fc region are deleted. E153. The FAP antigen-binding protein of any one of E135-E152, wherein said Fc region comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 348, 355, 356, 357, 358, 359, 360, 366, 370, or 374. E154. The FAP antigen-binding protein of any one of E116-E134, wherein said Fc region comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 348, 355, 356, 357, 358, 359, or 360. E155. The FAP antigen-binding protein of any one of E1-E154, further comprising a heavy chain constant domain. E156. The FAP antigen-binding protein of E155, wherein said constant domain is the constant domain of an IgA (for example IgA1 or lgA2), IgD, IgE, IgM, or IgG (for example IgG1, lgG2, lgG3, or lgG4). E157. The FAP antigen-binding protein of E155 or E156, wherein said constant domain is the constant domain of an IgG (for example IgG1, IgG2, IgG3, or IgG4), preferably a human IgG (for example, human IgG1, human IgG2, human IgG3, or human IgG4). E158. The FAP antigen-binding protein of any one of E155-E157, wherein said constant domain comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 349, 350, 351, 352, 353, 354, 361, 362, 363, 367, 371, or 375. E159. The FAP antigen-binding protein of any one of E155-E158, wherein said constant domain comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 349, 350, 351, 352, 353, 354, 361, 362, or 363. E160. The FAP antigen-binding protein of any one of E1-E159, further comprising a kappa or lambda light chain constant domain. E161. The FAP antigen-binding protein of any one of E1-E160, further comprising a kappa light chain constant domain that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:343 or 344. E162. The FAP antigen-binding protein of any one of E1-E160, further comprising a lambda light chain constant domain that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:345 or 346. E163. The FAP antigen-binding protein of any one of E1-E162, which is an antibody. E164. The FAP antigen-binding protein of any one of E1-E162, which is an antigen-binding fragment of an antibody, such as a Fab fragment. E165. The FAP antigen-binding protein of any one of E1-E162, which is an scFv. E166. The FAP antigen-binding protein of E165, wherein said scFv comprises a first linker between VH and VL. E167. The FAP antigen-binding protein of E166, wherein said first linker comprises: (a) a glycine rich peptide; (b) a peptide comprising glycine and serine; (c) a peptide comprising (Gly-Gly-Ser)n, wherein n is 1 , 2, 3, 4, 5, or 6 (SEQ ID NO: 388); (d) a peptide comprising (Gly-Gly-Gly-Ser)n, wherein n is 1 , 2, 3, 4, 5, or 6 (SEQ ID NO: 386); (e) a peptide comprising (Gly-Gly-Gly-Gly-Ser)n, wherein n is 1 , 2, 3, 4, 5, or 6 (SEQ ID NO: 387); or (f) a peptide comprising (Gly-Gly-Gly-Gly-Gln)n, wherein n is 1 , 2, 3, 4, 5, or 6 (SEQ ID NO: 389). E168. The FAP antigen-binding protein of E166 or E167, wherein said first linker comprises the amino acid sequence of (Gly-Gly-Gly-Gly-Ser)3(SEQ ID NO:387). E169. The FAP antigen-binding protein of any one of E165-E168, comprising a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:519. E170. The FAP antigen-binding protein of any one of E165-E168, comprising a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:520. E171. The FAP antigen-binding protein of any one of E165-E168, comprising a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:521. E172. The FAP antigen-binding protein of any one of E165-E168, comprising a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:518. E173. The FAP antigen-binding protein of any one of E165-E168, comprising a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:393. E174. The FAP antigen-binding protein of any one of embodiments E1-E162, which is a Fab. E175. The FAP antigen-binding protein of any one of E1-E174, wherein the antigen-binding protein binds to FAP with a KD value of or less than: about 200nM, about 150nM, about 100nM, about 90nM, about 80nM, about 70nM, about 60nM, about 50nM, about 40nM, about 30nM, about 25nM, about 20nM, about 15nM, about 10nM, about 9nM, about 8nM, about 7nM, about 6nM, about 5nM, about 4nM, about 3nM, about 2nM, about 1 nM, about 900pM, about 800pM, about 700pM, about 600pM, about 500pM, about 400pM, about 300pM, about 250pM, about 200pM, about 150pM, about 100pM, about 50pM, about 40pM, about 30pM, about 25pM, about 20pM, about 15pM, about 10pM, about 5pM, or about 1pM. E176. A FAP antigen-binding protein that competes for binding to FAP with any one of the FAP antigen-binding protein of E1-E175. E177. A FAP antigen-binding protein that binds to substantially the same epitope as any one of the FAP antigen-binding protein of E1-E175. E178. The FAP antigen-binding protein of any one of embodiments E1-E177, which is a bispecific molecule that further comprises a second antigen-binding moiety. E179. A nucleic acid comprising a nucleotide sequence encoding the FAP antigen-binding protein of any one of E1-E178. E180. A vector comprising the nucleic acid of E179. E181. A host cell comprising the nucleic acid of E179, or the vector of E180. E182. The host cell of E181, wherein said host cell is a mammalian cell. E183. The host cell of E182, wherein said host cell is a CHO cell or a HEK-293 cell, or an Sp2.0 cell. E184. A kit comprising (i) the FAP antigen-binding protein of any one of E1-E178; the nucleic acid of E179, the vector of E180, the host cell of E182 or E183, or a combination thereof, and (ii) instructions for use. E185. A pharmaceutical composition comprising (i) the FAP antigen-binding protein of any one of E1-E178; the nucleic acid of E179, the vector of E180, the host cell of E182 or E183, or a combination thereof; and (ii) a pharmaceutically acceptable carrier, excipient, or diluent. E185. A method of making the FAP antigen-binding protein of any one of E1-E178, comprising culturing the host cell of any one of E181-E181, under a condition wherein the FAP antigen-binding protein is expressed. E186. The method of E185, further comprising harvesting the expressed the FAP antigen-binding protein. E187. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the FAP antigen-binding protein of any one of E1-E178, or the pharmaceutical composition of E185. E188. The method of E187, wherein cancer is solid tumor. E189. The method of E187 or E188, wherein said cancer comprises stromal cells. E190. The method of any one of E187-E189, wherein said cancer comprises stromal cells that express FAP. E191. The method of any one of E187-190, wherein said subject is a human. E192. The method of any one of E187-E191, wherein said FAP antigen-binding protein or pharmaceutical composition is administered intravenously. E193. The method of any one of E187-E191, wherein said FAP antigen-binding protein or pharmaceutical composition is administered subcutaneously. E194. The method of any one of 187-193, wherein said FAP antigen-binding protein or pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months. E195. The FAP antigen-binding protein of any one of E1-E178, or the pharmaceutical composition of E185, for use as a medicament. E196. The FAP antigen-binding protein of any one of E1-E178, or the pharmaceutical composition of E185, for use in treating cancer in a subject. E197. Use of the FAP antigen-binding protein of any one of E1-E178, or the pharmaceutical composition of E185, in the manufacture of a medicament for treating cancer in a subject. E198. Use of the FAP antigen-binding protein of any one of E1-E178, or the pharmaceutical composition of E185, for treating cancer in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG.1A shows the crystal structure of FAP in complex with scFv 32211. FIG.1B shows the epitope and paratope residues and their interactions.

[0012] FIG.2A shows the crystal structure of FAP in complex with scFv 40828. FIG.2B shows the epitope and paratope residues and their interactions.

[0013] FIG.3A shows the crystal structure of FAP in complex with scFv 32229. FIG.3B shows the epitope and paratope residues and their interactions.

[0014] FIG.4A shows the crystal structure of FAP in complex with scFv 40827. FIG.4B shows the epitope and paratope residues and their interactions.

[0015] FIG.5 is an illustration of a bispecific molecule comprising an IgG moiety and two scFv moieties (IgG-scFv). A cysteine clamp may be introduced into scFv (represented as a horizontal line within scFv). The use (or non-use) of cysteine clamp may require evaluation of stability and biologically activities of the scFv. DETAILED DESCRIPTION 1. Overview

[0016] Targeting T-cell co-stimulatory molecules has shown great promise in treatment of cancer. However, agonists targeting these molecules also raise safety concerns such as systemic toxicity (see, e.g., Dahan, et al., Cancer Cell 29, 820–831 (2016). A preferred mechanism would be limiting the activation of T-cell co-stimulatory molecules within cancer microenvironment.

[0017] FAP is an attractive target for delivering agonists for T-cell co-stimulatory molecules to cancer tissues. FAP abundantly expressed in the stroma of many solid tumors by cancer-associated fibroblasts (CAFs). FAP is expressed selectively in reactive stromal fibroblasts of more than 90% of epithelial malignancies (primary and metastatic), including lung, colorectal, bladder, ovarian and breast carcinomas, and in malignant mesenchymal cells of bone and soft tissue sarcomas, while it is generally absent from normal adult tissues. FAP is also expressed on certain malignant tumor cells.

[0018] Accordingly, the FAP antigen-binding proteins disclosed herein are useful as a targeting moiety to deliver cancer treatment molecules such as agonists for T-cell co-stimulatory molecules. The T-cell co-stimulatory agonist can be engineered to be crosslinking dependent (also called clustering dependent), meaning that the activation of the T cell depends on the clustering of the T-cell co- stimulatory molecules. In the absence of the high level FAP (i.e., normal, non-malignant cells), minimal stimulation of T cells occurs due to lack of clustering, and immune activation and toxicity will be limited. In contrast, in cancer-associated fibroblasts (CAFs), FAP is highly expressed; therefore, through FAP-binding, large number of T cell agonists will be in proximity of each other, trigger receptor clustering and immune cell activation. The advantages of this strategy are twofold: systemic toxicities should be limited because activation will be largely confined to tissue expressing FAP, and tumor-mediated T-cell activation leads to killing of cancer cells.

[0019] The inventors also discovered that, while FAP is a membrane-bound protein, its extracellular domain could be shed and circulate in peripheral blood. Indeed, soluble FAP (sFAP) was detected in both healthy individuals as well as diseased subjects, including cancer patients. If a FAP antigen- binding protein can bind to sFAP and form a higher-order molecular complex (i.e., multiple sFAP molecules in complex with multiple copies of FAP antigen-binding proteins), systemic toxicity remains to be a risk due to potential activation of immune cells in peripheral blood. Therefore, in some circumstances, it is desirable to use a FAP antigen-binding protein that does not trigger T-cell co- stimulatory molecule crosslinking through sFAP binding.

[0020] Accordingly, the present disclosure provides FAP antigen-binding proteins that target cancer- associated fibroblasts. Such FAP antigen-binding molecules can be used to deliver cancer treatment molecules, such as agonists for T-cell co-stimulatory molecules, within cancer tissue, thus limiting systemic toxicity. 2. Antigen-binding Proteins 2.1 Antigen-binding Protein Types

[0021] The antigen-binding proteins of the present disclosure can take any one of many forms of antigen-binding proteins known in the art. In exemplary aspects, the antigen-binding protein is an antibody or immunoglobulin, or an antigen-binding fragment of an antibody or immunoglobulin, or an antibody protein product.

[0022] Collectively, antibodies form a family of plasma proteins known as immunoglobulins and comprise of immunoglobulin domains. (Janeway et al., Immunobiology: The Immune System in Health and Disease, 4thed., Elsevier Science Ltd. / Garland Publishing, 1999). As used herein, the term “antibody” refers to a protein having a conventional immunoglobulin format, comprising heavy and light chains, and comprising variable and constant regions. For example, an antibody may be an IgG which is a “Y-shaped” structure of two identical pairs of polypeptide chains, each pair having one “light” (typically having a molecular weight of about 25 kDa) and one “heavy” chain (typically having a molecular weight of about 50-70 kDa). An antibody has a variable region and a constant region. In IgG formats, the variable region is generally about 100-110 or more amino acids, comprises three complementarity determining regions (CDRs), is primarily responsible for antigen recognition, and substantially varies among other antibodies that bind to different antigens. The constant region allows the antibody to recruit cells and molecules of the immune system. The variable region is made of the N-terminal regions of each light chain and heavy chain, while the constant region is made of the C- terminal portions of each of the heavy and light chains. (Janeway et al., “Structure of the Antibody Molecule and the Immunoglobulin Genes”, Immunobiology: The Immune System in Health and Disease, 4thed. Elsevier Science Ltd. / Garland Publishing, (1999)).

[0023] Antibodies can comprise any constant region known in the art. Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including, but not limited to, IgM1 and IgM2. Embodiments of the present disclosure include all such classes or isotypes of antibodies. The light chain constant region can be, for example, a kappa- or lambda-type light chain constant region, e.g., a human kappa- or lambda-type light chain constant region. The heavy chain constant region can be, for example, an alpha-, delta-, epsilon-, gamma-, or mu-type heavy chain constant regions, e.g., a human alpha-, delta-, epsilon-, gamma-, or mu-type heavy chain constant region. Accordingly, in exemplary embodiments, the antibody is an antibody of isotype IgA, IgD, IgE, IgG, or IgM, including any one of IgG1, IgG2, IgG3 or IgG4.

[0024] The antibody can be a monoclonal antibody or a polyclonal antibody. In some embodiments, the antibody comprises a sequence that is substantially similar to a naturally-occurring antibody produced by a mammal, e.g., mouse, rabbit, goat, horse, chicken, hamster, human, and the like. In this regard, the antibody can be considered as a mammalian antibody, e.g., a mouse antibody, rabbit antibody, goat antibody, horse antibody, chicken antibody, hamster antibody, human antibody, and the like. In certain aspects, the antibody is a human antibody. In certain aspects, the antibody is a chimeric antibody or a humanized antibody. The term "chimeric antibody" refers to an antibody containing domains from two or more different antibodies. A chimeric antibody can, for example, contain the constant domains from one species and the variable domains from a second, or more generally, can contain stretches of amino acid sequence from at least two species. A chimeric antibody also can contain domains of two or more different antibodies within the same species. The term "humanized" when used in relation to antibodies refers to antibodies having at least CDR regions from a non-human source which are engineered to have a structure and immunological function more similar to true human antibodies than the original source antibodies. For example, humanizing can involve grafting a CDR from a non-human antibody, such as a mouse antibody, into a human antibody. Humanizing also can involve select amino acid substitutions to make a non-human sequence more similar to a human sequence.

[0025] An antibody can be cleaved into fragments by enzymes, such as, e.g., papain and pepsin. Papain cleaves an antibody to produce two Fab fragments and a single Fc fragment. Pepsin cleaves an antibody to produce a F(ab’)2fragment and a pFc’ fragment. In exemplary aspects of the present disclosure, the antigen-binding protein of the present disclosure comprises an antigen-binding fragment of an antibody. As used herein, “antigen-binding fragment” of an antibody refers to a portion of an antibody molecule that retains the ability to specifically bind to an antigen (preferably with substantially the same binding affinity). Examples of an antigen-binding fragment include but not limited to: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., 1989 Nature 341 :544-546), which consists of a VH domain.

[0026] The architecture of antibodies has been exploited to create a growing range of alternative formats that span a molecular-weight range of at least about 12–150 kDa and has a valency (n) range from monomeric (n = 1), to dimeric (n = 2), to trimeric (n = 3), to tetrameric (n = 4), and potentially higher; such alternative formats are referred to herein as “antibody protein products.”

[0027] The building block that is most frequently used to create novel antibody-based formats is the single-chain variable (V)-domain antibody fragment (scFv). Although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (see e.g., Bird et al. Science 242:423- 426 (1988) and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883).

[0028] Other forms of single chain antibody protein products, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibody protein products in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen-binding sites (see e.g., Holliger et al, 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al., 1994, Structure 2:1121 -1123).

[0029] Other antibody protein products include disulfide-bond stabilized scFv (ds-scFv), single chain Fab (scFab), as well as di- and multimeric antibody formats like dia-, tria- and tetra-bodies, or minibodies (miniAbs) that comprise different formats consisting of scFvs linked to oligomerization domains. The smallest fragments are VHH / VH of camelid heavy chain Abs as well as single domain Abs (sdAb). A peptibody or peptide-Fc fusion is yet another antibody protein product. The structure of a peptibody consists of a biologically active peptide grafted onto an Fc domain. Peptibodies are well- described in the art. See, e.g., Shimamoto et al., mAbs 4(5): 586-591 (2012).

[0030] Bispecific formats can generally be divided into five major classes: BsIgG, appended IgG, BsAb fragments, bispecific fusion proteins and BsAb conjugates. See, e.g., Spiess et al., Molecular Immunology 67(2) Part A: 97-106 (2015).

[0031] In exemplary aspects, the antigen-binding protein of the present disclosure comprises any one of these antibody protein products. In exemplary aspects, the antigen-binding protein of the present disclosure comprises any one of an scFv, Fab, Fv fragment, ds-scFv, scFab, dimeric antibody, multimeric antibody (e.g., a diabody, triabody, tetrabody), miniAb, peptibody, VHH / VH of camelid heavy chain antibody, sdAb, diabody; a triabody; a tetrabody; a bispecific or trispecific antibody, BsIgG, appended IgG, BsAb fragment, bispecific fusion protein, and BsAb conjugate.

[0032] In exemplary instances, the antigen-binding protein of the present disclosure comprises an antibody protein product in monomeric form, or polymeric, oligomeric, or multimeric form. In certain embodiments in which the antibody comprises two or more distinct antigen-binding regions fragments, the antibody is considered bispecific, trispecific, or multi-specific, or bivalent, trivalent, or multivalent, depending on the number of distinct epitopes that are recognized and bound by the antibody.

[0033] Many of the antigen-binding proteins disclosed herein comprise two different chains, one derived from the heavy chain of an antibody, and one derived from the light chain of an antibody. Although the heavy / light chain has been modified and is no longer the classical immunoglobulin heavy / light chain, for convenience, it is still generally called “heavy chain” or “HC” if it is based on heavy chain backbone, and “light chain” or “LC” if it is based on light chain backbone. For example, for tetravalent bispecific molecule IgG-scFv, the “HC” comprises an IgG heavy chain fused to an scFv. It would be apparent to a skilled artisan whether HC is a traditional immunoglobulin heavy chain or a modified version based on immunoglobulin heavy chain backbone. 2.2 Binding Location

[0034] Some exemplary antigen-binding proteins disclosed herein are characterized by the epitopes they bind to, or by the paratopes that they comprise. An “epitope” refers to the area or region of an antigen to which an antigen-binding protein specifically binds, e.g., an area or region comprising residues that interacts with the antigen-binding protein. Epitopes can be linear or conformational. Epitopes can be determined by any method well known in the art. For example, epitopes can be determined by conventional immunoassays. Alternatively, one may competitively screen antigen- binding proteins for binding to the same epitope. An approach to achieve this is to conduct competition and cross-competition studies to find antigen-binding proteins that compete or cross- compete with one another for binding to an antigen (such as FAP).

[0035] The term “paratope” is derived from the above definition of “epitope” by reversing the perspective, and refers to the area or region of an antigen-binding protein which is involved in binding of an antigen, e.g., an area or region comprising residues that interacts with the antigen. A paratope may be linear or conformational (such as discontinuous residues in CDRs).

[0036] The epitope / paratope can be defined and characterized at different levels of detail using a variety of experimental and computational epitope mapping methods. The experimental methods include mutagenesis, X-ray crystallography, Nuclear Magnetic Resonance (NMR) spectroscopy, Hydrogen / deuterium exchange Mass Spectrometry (HX-MS), cryo-EM, and various competition binding methods. As each method relies on a unique principle, the description of an epitope is linked to the method by which it has been determined. Thus, the epitope / paratope for a given binding pair will be defined differently depending on the mapping method employed.

[0037] At its most detailed level, the epitope / paratope for the interaction between the antigen and the antigen-binding protein can be defined by the spatial coordinates defining the atomic contacts present in the interaction, as well as information about their relative contributions to the binding thermodynamics. At one level, an epitope / paratope residue can be characterized by the spatial coordinates defining the atomic contacts between the binding pair. In one aspect, the epitope / paratope residue can be defined by a specific criterion, e.g., distance between atoms in the antigen and the antigen-binding protein (e.g., a distance of equal to or less than 4.5 Å from a heavy atom of the antigen and a heavy atom of the antigen-binding protein ("contact" residues)). In another aspect, an epitope / paratope residue can be characterized as participating in a hydrogen bond interaction with the cognate antibody / antigen, or with a water molecule that is also hydrogen bonded to the antigen / antigen-binding protein (water-mediated hydrogen bonding). In another aspect, an epitope / paratope residue can be characterized as forming a salt bridge with a residue of the cognate antibody / antigen. In yet another aspect, an epitope / paratope residue can be characterized as a residue having a non-zero change in buried surface area (BSA) due to the interaction between the antigen and the antigen-binding protein.

[0038] At a further less detailed level, epitope / paratope can be characterized through function, e.g., by competition binding with other antigen-binding molecules. The epitope / paratope can also be defined more generically as comprising amino acid residues for which substitution by another amino acid will alter the characteristics of the interaction between the binding pair (e.g., alanine scanning).

[0039] In the context of an X-ray derived crystal structure or cryo-EM structure, as exemplified herein with respect to FAP antigen-binding proteins, unless otherwise specified, a FAP epitope residue refers to a FAP residue: (i) having a heavy atom (i.e., a non-hydrogen atom) that is within a distance of 4.5 Å from a heavy atom of the antigen-binding protein (also called “contact” residues); (ii) participating in a hydrogen bond with a residue of the antigen-binding protein, or with a water molecule that is also hydrogen bonded to the antigen-binding protein (water- mediated hydrogen bonding), (iii) participating in a salt bridge to a residue of the antigen-binding protein, and / or (iv) having a non-zero change in buried surface area (BSA) due to interaction with the antigen-binding protein. In general, a cutoff is imposed for BSA to avoid inclusion of residues that have minimal interactions. Therefore, unless otherwise specified, epitope residues under category (iv) are selected if it has a BSA of 20 Å2or greater, or is involved in electrostatic interactions when the antigen-binding protein binds to FAP. Similarly, in the context of an X-ray derived crystal structure or cryo-EM structure, unless otherwise specified or contradicted by context, a paratope residue, refers to an antigen-binding protein residue (i) having a heavy atom (i.e., a non-hydrogen atom) that is within a distance of 4.5 Å from a heavy atom of FAP (also called “contact” residues), (ii) participating in a hydrogen bond with an antigen residue, or with a water molecule that is also hydrogen bonded to FAP (water-mediated hydrogen bonding), (iii) participating in a salt bridge to a residue of FAP, and / or (iv) having a non-zero change in buried surface area due to interaction with FAP. Again, unless otherwise specified, paratope residues under category (iv) are selected if it has a BSA of 20 Å2or greater, or is involved in electrostatic interactions when the antigen-binding protein binds to FAP.

[0040] Dependent on the epitope mapping method used, and obtained at different levels of detail, it follows that comparison of epitopes for different antigen-binding protein on the same antigen can similarly be conducted at different levels of detail. For example, epitopes described on the amino acid level, e.g., determined from an X-ray or cryo-EM structure, are said to be identical if they contain the same set of amino acid residues. Epitopes are said to be separate (unique) if no amino acid residue is shared by the epitopes. Epitopes characterized by competition binding are said to be overlapping if the binding of two molecules are mutually exclusive, i.e., binding of one molecule excludes simultaneous or consecutive binding of the other molecule; and epitopes are said to be separate (unique) if the antigen is able to accommodate binding of both molecules simultaneously.

[0041] FAP exhibits prolyl endopeptidase activity and is active as a homodimer with specificity for type I collagen. For tumor-targeting, it may be desirable that the antigen-binding protein does not bind to an epitope residue that is located at or near the dimer interface. This is because “valency” may play a role in FAP-mediated receptor clustering. If the FAP binder binds at or near the dimer interface, then only one copy of the FAP binder can bind to each FAP dimer. If the FAP binder binds to an area that is not near or at the dimer interface (such as the exemplary FAP binding proteins disclosed herein), then two copies of the FAP binder can simultaneously bind to each FAP dimer. Simultaneous binding of two FAP binders to a FAP dimer may enhance the ability of T cell co-stimulatory molecule to cluster (crosslink).

[0042] In addition to membrane-bound FAP, FAP can be shed from the membrane and exists as a soluble form in plasma. As discussed above, for tumor-targeting, strong binding of soluble FAP is not desirable, as binding to soluble FAP in plasma can activate circulating immune cells (e.g., B cells) in plasma, raising the potential risk of systemic toxicity. Exemplary FAP binding proteins disclosed herein are generally selected to show strong binding to membrane-bound FAP and weak binding to soluble FAP. In particular, it was found that molecules that bind to Bin A (Table 5 in Examples) showed very low level of soluble FAP binding. Preliminary observation based on negative stain EM showed that if a FAP antigen-binding protein binds to sFAP and forms molecular complexes (i.e., multiple sFAP molecules in complex with multiple copies of FAP antigen-binding proteins), systemic toxicity remains to be a risk. Therefore, if a FAP antigen-binding protein has two arms (such as a traditional Y-shaped immunoglobulin), preferred epitope location should be at a position where the two arms cannot each bind to a sFAP molecule simultaneously. Simultaneous binding of a sFAP molecule on each arm could increase the risk of forming molecular complexes. For example, it is believed that epitope Bin A’s location makes it physically difficult to accommodate two FAPs, one on each arm.

[0043] In some embodiments, the present disclosure provides a FAP antigen-binding protein that binds to an epitope that comprises residues V275, R175, F181, Q182, I183, D178, F185, P179, and Y274. In certain embodiments, the epitope may further comprise one or more residues selected from the group consisting of: Q174, W327, P277, and Q278. In certain embodiments, the epitope may further comprise one or more residues selected from the group consisting of: P272, P180, I267, G276, D326, and A273. These epitope residues are numbered according to the numbering of SEQ ID NO:394 (human FAP). Corresponding residues from other FAP homologs, isoforms, variants, or fragments can be identified according to sequence alignment or structural alignment that is known in the art. For example, alignments can be done by hand or by using well-known sequence alignment programs such as ClustalW2, or "BLAST 2 Sequences" using default parameters. As exemplified by the structural data, V275, R175, F181, Q182, I183, D178, F185, P179, and Y274 were found to be “primary” residues for scFv32211 binding; Q174, W327, P277, and Q278 were found to be “contributing” residues for scFv32211 binding; and P272, P180, I267, G276, D326, and A273, while in “contact” with residues of scFv32211, were found to be “optional” residues for scFv32211 binding.

[0044] Based on the structural studies, one or more of the following substitutions of “primary” residues would likely substantially disrupt the binding of scFv32211 binding to FAP: (1) R175 is replaced with A, N, D, C, Q, E, G, I, L, M, F, P, S, T. W, T, or V; (2) D178 is replaced with R, K, A, N, C, Q, G, I, L, M, F, P, S, T, W, Y, or V; (3) P179 is replaced with R, K, N, Q, I, M, F, W, Y, D, E, or H; (4) F181 is replaced with R, K, A, N, C, D, E, Q, G, I, L, M, P, S, T, V, or H; (5) F185 is replaced with R, K, A, N, C, D, E, Q, G, I, L, M, P, S, T, V or H; (6) Y274 is replaced with R, K, A, G, I, L, M, P, S, T, V, H, F, or W; or (7) V275 is replaced with R, K, N, Q, I, L, M, H, F, W, Y, D, or E. One or more of the following substitutions of “secondary” residues would likely substantially disrupt the binding of scFv32211 binding to FAP: (8) Q174 is replaced with A, C, G, I, L, M, F, P, W, Y, or V; (9) P277 is replaced with R, K, N, Q, I, L, M, H, F, W, Y, D, or E; or (10) Q278 is replaced with A, R, K, I, L, M, F, W, or Y. One or more of the following substitutions of “secondary” residues would likely substantially disrupt the binding of scFv32211 binding to FAP: (11) A273 is replaced with R, K, N, Q, I, M, F, W, Y, D, E, or H; or (12) G276 is replaced R, K, N, Q, I, L. M, H, F, W, Y, D, or E.

[0045] In some embodiments, the present disclosure provides a FAP antigen-binding protein that binds to an epitope that comprises residues E325, D331, Q336, I320, R324, E302, R303, and T335. In certain embodiments, the epitope may further comprise one or more residues selected from the group consisting of: K381, D322, P333, and F357. In certain embodiments, the epitope may further comprise one or more residues selected from the group consisting of: K219, D326, W327, A361, I362, S363, Y364, I380, D382, F323, and H338. These epitope residues are numbered according to the numbering of SEQ ID NO:394 (human FAP). Corresponding residues from other FAP homologs, isoforms, variants, or fragments can be identified according to sequence alignment or structural alignment that is known in the art. For example, alignments can be done by hand or by using well- known sequence alignment programs such as ClustalW2, or "BLAST 2 Sequences" using default parameters. As exemplified by the structural data, E325, D331, Q336, I320, R324, E302, R303, and T335 were found to be “primary” residues for scFv40828 binding; K381, D322, P333, and F357 were found to be “contributing” residues for scFv40828 binding; and K219, D326, W327, A361, I362, S363, Y364, I380, D382, F323, and H338, while in “contact” with residues of scFv40828, were found to be “optional” residues for scFv40828 binding.

[0046] Based on the structural studies, one or more of the following substitutions of “primary” residues would likely substantially disrupt the binding of scFv40828 binding to FAP: (1) E302 is replaced with A; (2) R303 is replaced with A; (3) I320 is replaced with A; (4) R324 is replaced with A; (5) E325 is replaced with A; (6) D331 is replaced with A; (7) T335 is replaced with A; or (8) Q336 is replaced with A. One or more of the following substitutions of “secondary” residues would likely substantially disrupt the binding of scFv40828 binding to FAP: (9) D322 is replaced with A; or (10) P333 is replaced with W, R, K, F, H, I, M, or Y; F357 is replaced with A. One or more of the following substitutions of “secondary” residues would likely substantially disrupt the binding of scFv40828 binding to FAP: (11) Y364 is replaced with A; or (12) D382 is replaced with W, R, K, F, H, I, M, or Y.

[0047] In some embodiments, the present disclosure provides a FAP antigen-binding protein that binds to an epitope that comprises residues S86, E82, I181, T83, Q85, Q65, K486, N80, T88, I485 and I487. In certain embodiments, the epitope may further comprise one or more residues selected from the group consisting of: V77, G84, Y79, and Y87. In certain embodiments, the epitope may further comprise one or more residues selected from the group consisting of: E66, Y67, S71, D73, N75, S136, and L488. These epitope residues are numbered according to the numbering of SEQ ID NO:394 (human FAP). Corresponding residues from other FAP homologs, isoforms, variants, or fragments can be identified according to sequence alignment or structural alignment that is known in the art. For example, alignments can be done by hand or by using well-known sequence alignment programs such as ClustalW2, or "BLAST 2 Sequences" using default parameters. As exemplified by the structural data, S86, E82, I181, T83, Q85, Q65, K486, N80, T88, I485 and I487 were found to be “primary” residues for scFv32229 binding; V77, G84, Y79, and Y87 were found to be “contributing” residues for scFv32229 binding; and E66, Y67, S71, D73, N75, S136, and L488, while in “contact” with residues of scFv32229, were found to be “optional” residues for scFv32229 binding.

[0048] Based on the structural studies, one or more of the following substitutions of “primary” residues would likely substantially disrupt the binding of scFv32229 binding to FAP: (1) Q65 is replaced with A; (2) N80 is replaced with A; (3) E82 is replaced with A; (4) T83 is replaced with A; (5) Q85 is replaced with A; (6) S86 is replaced with A: (7) T88 is replaced with A; (8) I485 is replaced with A; or (9) K486 is replaced with A. One or more of the following substitutions of “secondary” residues would likely substantially disrupt the binding of scFv32229 binding to FAP: (10) V77 is replaced with A; (11) Y79 is replaced with A; (12) G84 is replaced with A; or (13) Y87 is replaced with A. One or more of the following substitutions of “secondary” residues would likely substantially disrupt the binding of scFv32229 binding to FAP: (14) N75 is replaced with F, Y, or W.

[0049] In some embodiments, the present disclosure provides a FAP antigen-binding protein that binds to an epitope that comprises residues K381, K371, E414, S428, Q389, Y432, I390, P434, and K436. In certain embodiments, the epitope may further comprise one or more residues selected from the group consisting of: I427, I388, G430, P433, and I426. In certain embodiments, the epitope may further comprise one or more residues selected from the group consisting of: W395, S435, Y379, N386, A387, and S392. These epitope residues are numbered according to the numbering of SEQ ID NO:394 (human FAP). Corresponding residues from other FAP homologs, isoforms, variants, or fragments can be identified according to sequence alignment or structural alignment that is known in the art. For example, alignments can be done by hand or by using well-known sequence alignment programs such as ClustalW2, or "BLAST 2 Sequences" using default parameters. As exemplified by the structural data, K381, K371, E414, S428, Q389, Y432, I390, P434, and K436 were found to be “primary” residues for scFv40827 binding; I427, I388, G430, P433, and I426 were found to be “contributing” residues for scFv40827 binding; and W395, S435, Y379, N386, A387, and S392, while in “contact” with residues of scFv40827, were found to be “optional” residues for scFv40827 binding.

[0050] Based on the structural studies, one or more of the following substitutions of “primary” residues would likely substantially disrupt the binding of scFv40327 binding to FAP: (1) K371 is replaced with A; (2) K381 is replaced with A; (3) E414 is replaced with A; (4) I390 is replaced with A; (5) Y432 is replaced with A; (6) P434 is replaced with F; or (7) K436 is replaced with A. One or more of the following substitutions of “secondary” residues would likely substantially disrupt the binding of scFv40827 binding to FAP: (8) I388 is replaced with A; (9) I427 is replaced with A; (10) G430 is replaced with A, or (11) P433 is replaced with F.

[0051] Disruption of binding can be assessed by measuring the affinity (such as KD value) of the antigen-binding molecule to the epitope; or by competition assays that are known in the art. 2.3 Structure of FAP Antigen-binding Proteins

[0052] In some embodiments, the present disclosure provides a FAP antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said FAP antigen-binding protein comprises the following paratope residues (VH and VL numberings according to Kabat): (1) H33 is Arg, Lys, Gln, or Asn; (2) H94 is; Arg, Lys, Gln, or Asn; (3) H97 is Gly or Ala; (4) H98 is Tyr, Trp, Phe, Thr, or Ser; (5) H100B is Tyr, Trp, Phe, Thr, or Ser, (6) H100C is Tyr, Trp, Phe, Thr, or Ser; (7) L53 is Gln, Asn, or Glu; (8) L54 is Arg, Lys, Gln, or Asn; and (9) L60 is Asp, Glu, or Asn. Based on structural studies, these paratope residues were found to be “primary” paratope residues from clone scFv32211 that bind to FAP. Preferably, (1) H33 is Arg or Lys; (2) H94 is Arg or Lys; (3) H97 is Gly or Ala; (4) H98 is Tyr or Phe; (5) H100B is Tyr or Phe; (6) H100C is Tyr or Phe; (7) L53 is Gln or Asn; (8) L54 is Arg or Lys; and (9) L60 is Asp or Glu. More preferably, (1) H33 is Arg; (2) H94 is Arg; (3) H97 is Gly; (4) H98 is Tyr; (5) H100B is Tyr; (6) H100C is Tyr; (7) L53 is Gln; (8) L54 is Arg; and (9) L60 is Asp.

[0053] The FAP antigen-binding protein may further comprise the following paratope residues: (VH and VL numberings according to Kabat): (10) H31 is Asn, Gln, His, Asp, Lys, or Arg; (11) H34 is Val, Ile, Leu, Met, Phe, Ala, or Norleucine; (12) L49 is Tyr, Trp, Phe, Thr, or Ser; and (13) L50 is Ser or Thr. Based on structural studies, these paratope residues were found to be “contributing” residues from clone scFv32211 that bind to FAP. Preferably, (10) H31 is Asn or Gln; (11) H34 is Val or Leu; (12) L49 is Tyr or Phe; and (13) L50 is Ser or Thr. More preferably, (10) H31 is Asn; (11) H34 is Val; (12) L49 is Tyr; and (13) L50 is Ser.

[0054] The FAP antigen-binding protein may further comprise the following paratope residues: (VH and VL numberings according to Kabat): (14) H27 is Phe, Leu, Val, Ile, Ala, or Tyr; (15) H28 is Ser or Thr; (16) H30 is Ser or Thr, (17) H95 is Ile, Leu, Val, Met, Ala, Phe, or Norleucine; (18) H96 is Gly or Ala; (19) H101 is Asp, Glu, or Asn; and (20) L52 is Asn, Gln, His, Asp, Lys, or Arg. Based on structural studies, these paratope residues were found to be “optional” residues from clone scFv32211 that bind to FAP. Preferably, (14) H27 is Phe or Tyr; (15) H28 is Ser or Thr; (16) H30 is Ser or Thr, (17) H95 is Ile or Leu; (18) H96 is Gly or Ala; (19) H101 is Asp or Glu; and (20) L52 is Asn or Gln. More preferably, (14) H27 is Phe; (15) H28 is Ser; (16) H30 is Ser, (17) H95 is Ile; (18) H96 is Gly; (19) H101 is Asp; and (20) L52 is Asn.

[0055] Based on structural studies, it was discovered that, for scFv32211, among six complementarity determining regions (CDRs), CDR-H1, CDR-H3, and CDR-L2 are responsible for contacting FAP residues. In additional, VL framework residue L60 (kabat numbering) also forms a salt bridge with FAP residue R175. Accordingly, in certain embodiments, the FAP antigen-binding protein comprises (a) a VH that comprises: (i) a complementarity determining region (CDR)-H1 comprising any one of SEQ ID NOs: 398-402; and (ii) a CDR-H3 comprising any one of SEQ ID NOs: 408-412; (b) a VL that comprises a CDR-L2 comprising any one of SEQ ID NOs: 418-422; and (c) said VL further comprises a D at position L60. In certain embodiments, said CDR-H1, CDR-H3, CDR-L2, and residue D at L60 contact one or more of FAP residues selected from the group consisting of: Q174, R175, D178, P179, P180, F181, Q182, I183, F185, I267, P272, A273, Y274, V275, G276, P277, Q278, D326, and W327 (numbering according to SEQ ID NO:394).

[0056] In some embodiments, the present disclosure provides a FAP antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said FAP antigen-binding protein comprises the following paratope residues (VH and VL numberings according to Kabat): (1) H31 is Arg, Lys, Gln, or Asn; (2) H98 is Tyr, Trp, Phe, Thr, or Ser; (3) H99 is  Tyr, Trp, Phe, Thr, or Ser; (4) H100 is Tyr, Trp, Phe, Thr, or Ser; and (5) H101 is Asp, Glu, or Asn. Based on structural studies, these paratope residues were found to be “primary” paratope residues from clone scFv40828 that bind to FAP. Preferably, (1) H31 is Arg or Lys; (2) H98 is Tyr or Phe; (3) H99 is Tyr or Phe; (4) H100 is Tyr or Phe; and (5) H101 is Asp or Glu. More preferably, (1) H31 is Arg; (2) H98 is Tyr; (3) H99 is Tyr; (4) H100 is Tyr; and (5) H101 is Asp.

[0057] The FAP antigen-binding protein may further comprise the following paratope residues: (VH and VL numberings according to Kabat): (6) H28 is Thr or Ser; and (7) H100A is Tyr, Trp, Phe, Thr, or Ser. Based on structural studies, these paratope residues were found to be “contributing” residues from clone scFv40828 that bind to FAP. Preferably, (6) H28 is Thr or Ser; and (7) H100A is Tyr or Phe. More preferably, (6) H28 is Thr; and (7) H100A is Tyr.

[0058] The FAP antigen-binding protein may further comprise the following paratope residues: (VH and VL numberings according to Kabat): (8) H32 is Tyr, Trp, Phe, Thr, or Ser; (9) H96 is Pro or Ala; (10) H97 is Ser or Thr; (11) H100C is Tyr, Trp, Phe, Thr, or Ser; (12) L32 is Phe, Leu, Val, Ile, Ala, or Tyr; and (13) L49 is Tyr, Trp, Phe, Thr, or Ser. Based on structural studies, these paratope residues were found to be “optional” residues from clone scFv40828 that bind to FAP. Preferably, (8) H32 is Tyr or Phe; (9) H96 is Pro or Ala; (10) H97 is Ser or Thr; (11) H100C is Tyr or Phe; (12) L32 is Phe or Tyr; and (13) L49 is Tyr or Phe. More preferably, (8) H32 is Tyr; (9) H96 is Pro; (10) H97 is Ser; (11) H100C is Tyr; (12) L32 is Phe; and (13) L49 is Tyr.

[0059] Based on structural studies, it was discovered that, for scFv40828, among six complementarity determining regions (CDRs), CDR-H1, CDR-H3, and CDR-L2 are responsible for contacting FAP residues. Accordingly, in certain embodiments, the FAP antigen-binding protein comprises (a) a VH that comprises: (i) a complementarity determining region (CDR)-H1 comprising any one of SEQ ID NOs: 428-432; and (ii) a CDR-H3 comprising any one of SEQ ID NOs: 438-442; and (b) a VL that comprises a CDR-L2 comprising any one of SEQ ID NOs: 448-452. In certain embodiments, said CDR-H1, CDR-H3, and CDR-L2 contact one or more of FAP residues selected from the group consisting of: K219, E302, R303, I320, D322, F323, R324, E325, D326, W327, D331, P333, T335, Q336, H338, F357, A361, I362, S363, Y364, I380, K381, and D382 (numbering according to SEQ ID NO:394).

[0060] In some embodiments, the present disclosure provides a FAP antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said FAP antigen-binding protein comprises the following paratope residues (VH and VL numberings according to Kabat): (1) H31 is Asn, Gln, His, Asp, Lys, or Arg; (2) H33 is Gly, or Ala; (3) H52A is Tyr, Trp, Phe, Thr, or Ser; (4) H55 is Arg, Lys, Gln, or Asn; (5) H56 is Asn, Gln, His, Asp, Lys, or Arg; (6) H95 is Asp, Glu, or Asn; (7) H100 is Gly or Ala; (8) L32 is Tyr, Trp, Phe, Thr, or Ser; (9) L91 is Phe, Leu, Val, Ile, Ala, or Tyr; and (10) L95 is Tyr, Trp, Phe, Thr, or Ser. Based on structural studies, these paratope residues were found to be “primary” paratope residues from clone scFv32229 that bind to FAP. Preferably, (1) H31 is Asn or Gln; (2) H33 is Gly, or Ala; (3) H52A is Tyr or Phe; (4) H55 is Arg or Lys; (5) H56 is Asn or Gln; (6) H95 is Asp or Glu; (7) H100 is Gly or Ala; (8) L32 is Tyr or Phe; (9) L91 is Phe or Tyr; and (10) L95 is Tyr or Phe. More preferably, (1) H31 is Asn; (2) H33 is Gly; (3) H52A is Tyr; (4) H55 is Arg; (5) H56 is Asn; (6) H95 is Asp; (7) H100 is Gly; (8) L32 is Tyr; (9) L91 is Phe; and (10) L95 is Tyr.

[0061] The FAP antigen-binding protein may further comprise the following paratope residues: (VH and VL numberings according to Kabat): (11) H28 is Thr or Ser; (12) H32 is Tyr, Trp, Phe, Thr, or Ser; (13) H52 is Trp, Tyr, or Phe; (14) L30 is Tyr, Trp, Phe, Thr, or Ser; and (15) L96 is Trp, Tyr, or Phe. Based on structural studies, these paratope residues were found to be “contributing” residues from clone scFv32229 that bind to FAP. Preferably, (11) H28 is Thr or Ser; (12) H32 is Tyr or Phe; (13) H52 is Trp or Tyr; (14) L30 is Tyr or Phe; and (15) L96 is Trp or Tyr. More preferably, (11) H28 is Thr; (12) H32 is Tyr; (13) H52 is Trp; (14) L30 is Tyr; and (15) L96 is Trp.

[0062] The FAP antigen-binding protein may further comprise the following paratope residues: (VH and VL numberings according to Kabat): (16) H30 is Asn, Gln, His, Asp, Lys, or Arg; (17) H53 is Asp, Glu, or Asn; (18) H96 is Gly or Ala; (19) H97 is Ser or Thr; (20) H98 is Gly or Ala; (21) H99 is Gly or Ala; and (22) L56 is Ser or Thr. Based on structural studies, these paratope residues were found to be “optional” residues from clone scFv32229 that bind to FAP. Preferably, (16) H30 is Asn or Gln; (17) H53 is Asp or Glu; (18) H96 is Gly or Ala; (19) H97 is Ser or Thr; (20) H98 is Gly or Ala; (21) H99 is Gly or Ala; and (22) L56 is Ser or Thr. More preferably, (16) H30 is Asn; (17) H53 is Asp; (18) H96 is Gly; (19) H97 is Ser; (20) H98 is Gly; (21) H99 is Gly; and (22) L56 is Ser.

[0063] Based on structural studies, it was discovered that, for scFv32229, all six complementarity determining regions (CDRs), CDR-H1, CDR-H2, CDR-H3, and CDR-L2 contain residues that contact FAP residues. Accordingly, in certain embodiments, the FAP antigen-binding protein comprises (a) a VH that comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 458-462; (ii) a CDR-H3 comprising any one of SEQ ID NOs: 463-467; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 468-472; and (b) a VL that comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 473-487; (ii) a CDR-L2 comprising any one of SEQ ID NOs: 478-482; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 483-487. In certain embodiments, said CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 contact one or more of FAP residues selected from the group consisting of: Q65, N75, V77, Y79, N80, E82, T83, G84, Q85, S86, Y87, T88, I485, and K486 (numbering according to SEQ ID NO:394).

[0064] In some embodiments, the present disclosure provides a FAP antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said FAP antigen-binding protein comprises the following paratope residues (VH and VL numberings according to Kabat): (1) H28 is Thr or Ser; (2) H53 is Asp, Glu, or Asn; (3) H96 is Arg, Lys, Gln, or Asn; (4) H99 is Tyr, Trp, Phe, Thr, or Ser; (5) H100A is Tyr, Trp, Phe, Thr, or Ser; (6) H100B is Tyr, Trp, Phe, Thr, or Ser; and (7) H100C is Tyr, Trp, Phe, Thr, or Ser. Based on structural studies, these paratope residues were found to be “primary” paratope residues from clone scFv40827 that bind to FAP. Preferably, (1) H28 is Thr or Ser; (2) H53 is Asp or Glu; (3) H96 is Arg or Lys; (4) H99 is Tyr or Phe; (5) H100A is Tyr or Phe; (6) H100B is Tyr or Phe; and (7) H100C is Tyr or Phe. More preferably, (1) H28 is Thr; (2) H53 is Asp; (3) H96 is Arg; (4) H99 is Tyr; (5) H100A is Tyr; (6) H100B is Tyr; and (7) H100C is Tyr.

[0065] The FAP antigen-binding protein may further comprise the following paratope residues: (VH and VL numberings according to Kabat): (8) H31 is Ser or Thr; (9) H52 is Trp, Tyr, or Phe; (10) H97 is Leu, Norleucine, Ile, Val, Met, Ala, or Phe; (11) H98 is Gln, Asn, or Glu; (12) L32 is Leu, Norleucine, Ile, Val, Met, Ala, or Phe; (13) L91 is Tyr, Trp, Phe, Thr, or Ser; and (14) L96 is Trp, Tyr, or Phe. Based on structural studies, these paratope residues were found to be “contributing” residues from clone scFv40827 that bind to FAP. Preferably, (8) H31 is Ser or Thr; (9) H52 is Trp or Tyr; (10) H97 is Leu or Ile; (11) H98 is Gln or Asn; (12) L32 is Leu or Ile; (13) L91 is Tyr or Phe; and (14) L96 is Trp or Tyr. More preferably, (8) H31 is Ser; (9) H52 is Trp; (10) H97 is Leu; (11) H98 is Gln; (12) L32 is Leu; (13) L91 is Tyr; and (14) L96 is Trp.

[0066] The FAP antigen-binding protein may further comprise the following paratope residues: (VH and VL numberings according to Kabat): (15) H30 is Ser or Thr; (16) H95 is Asp, Glu, or Asn; (17) H100 is Asp, Glu, or Asn; and (18) L30 is Tyr, Trp, Phe, Thr, or Ser. Based on structural studies, these paratope residues were found to be “optional” residues from clone scFv40827 that bind to FAP. Preferably, (15) H30 is Ser or Thr; (16) H95 is Asp and Glu; (17) H100 is Asp or Glu; and (18) L30 is Tyr and Phe. More preferably, (15) H30 is Ser; (16) H95 is Asp; (17) H100 is Asp; and (18) L30 is Tyr.

[0067] Based on structural studies, it was discovered that, for scFv32229, all six complementarity determining regions (CDRs), CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 contain residues that contact FAP residues. Accordingly, in certain embodiments, the FAP antigen-binding protein comprises (a) a VH that comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 488-492; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 493-497; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 498-502; and (b) a VL that comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 503-507; and (ii) a CDR-L3 comprising any one of SEQ ID NOs: 513-517. In certain embodiments, said CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 contact one or more of FAP residues selected from the group consisting of: K381, K371, E414, S428, Q389, Y432, I390, P434, K436, I427, I388, G430, P433, I429, W395, S435, Y379, N386, A387, and S392 (numbering according to SEQ ID NO:394).

[0068] As used herein, “Complementarity Determining Regions” (CDRs) can be identified according to the definitions of the Kabat, Chothia, the accumulation of both Kabat and Chothia, AbM, contact, North, and / or conformational definitions or any method of CDR determination well known in the art. See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed. (hypervariable regions); Chothia et al., 1989, Nature 342:877-883 (structural loop structures). The identity of the amino acid residues in a particular antibody that make up a CDR can be determined using methods well known in the art. AbM definition of CDRs is a compromise between Kabat and Chothia and uses Oxford Molecular’s AbM antibody modeling software (Accelrys®). The “contact” definition of CDRs is based on observed antigen contacts, set forth in MacCallum et al., 1996, J. Mol. Biol., 262:732-745. The “conformational” definition of CDRs is based on residues that make enthalpic contributions to antigen binding (see, e.g., Makabe et al., 2008, J. Biol. Chem., 283:1156-1166). North has identified canonical CDR conformations using a different preferred set of CDR definitions (North et al., 2011, J. Mol. Biol.406: 228-256). In another approach, referred to herein as the “conformational definition” of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding (Makabe et al., 2008, J Biol. Chem.283:1156-1166). Martin definition (also called enhanced Chothia definition) combines the Kabat and Chothia definitions and differs from them only in the heavy chain, where CDR-H1 includes all residues of Kabat and Chothia while CDR-H2 is seven residues shorter than that defined by Kabat (Martin, Bioinformatics tools for antibody engineering. Handbook of Therapeutic Antibodies. Weinheim: Wiley-VCH Verlag GmbH; (2008). p.95–117; see also the database maintained by the Institute of Structural and Molecular Biology at the University College London, http: / / www.bioinf.org.uk / abs / #cdrid). Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. For example, “combined” CDRs may also be used. Therefore, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. For any given embodiment containing more than one CDR, the CDRs (or other residue of the antibody) may be defined in accordance with any of Kabat, Chothia, North, AbM, Contact, IMGT, Martin, combined Kabat and Chothia, and / or conformational definitions.

[0069] For example, the following Table shows several commonly used definitions of CDRs: Loop Kabat AbM Chothia1Contact2IMGT 1. some of these definitions (particularly for Chothia loops) vary depending on the individual publication examined. Some papers describe Chothia CDRs as: CDR-L1:L24-34; CDR-L2:L50-56; CDR-L3:L89-97; CDR-H1:H26-32; CDR-H2:H52-56; CDR-H3:H95-102. 2. Any of the numbering schemes can be used for these CDR definitions, except the contact definition uses the Chothia or Martin (Enhanced Chothia) definition. 3. The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop. (This is because the Kabat numbering scheme places the insertions at H35A and H35B.)

[0070] The CDR sequences provided in the Sequence Tables are based on the Kabat definition. However, other definitions for CDRs may also be used. Accordingly, in some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR- H3 of SEQ ID NO: 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 332, 334, 335, 339, or 341; and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 333, 336, 337, 338, 340, or 342. In some embodiments, the three heavy chain CDRs and three light chain CDRs come from the same clone as shown in Sequence Table B. In exemplary embodiments, the CDRs are defined according to Kabat, Chothia, AbM, contact, or IMGT.

[0071] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:197; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:198. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0072] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:199; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:200. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0073] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:201; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:202. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0074] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:203; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:204. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0075] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:205; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:206. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0076] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:207; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:208. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0077] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:209; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:210. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0078] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:211; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:212. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0079] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:213; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:214. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0080] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:215; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:216. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0081] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:217; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:218. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0082] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:219; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:220. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0083] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:221; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:222. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0084] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:223; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:224. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0085] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:225; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:226. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0086] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:227; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:228. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0087] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:229; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:230. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0088] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:231; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:232. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0089] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:233; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:234. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0090] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:235; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:236. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0091] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:237; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:238. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0092] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:239; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:240. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0093] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:241; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:242. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0094] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:243; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:244. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0095] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:245; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:246. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0096] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:247; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:248. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0097] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:249; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:250. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0098] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:251; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:252. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0099] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:253; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:254. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0100] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:255; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:256. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0101] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:257; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:258. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0102] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:259; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:260. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0103] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:261; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:262. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0104] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:263; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:264. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0105] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:265; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:266. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0106] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:267; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:268. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0107] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:269; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:270. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0108] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:271; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:272. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0109] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:273; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:274. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0110] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:275; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:276. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0111] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:277; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:278. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0112] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:279; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:280. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0113] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:281; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:282. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0114] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:283; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:284. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0115] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:285; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:286. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0116] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:287; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:288. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0117] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:289; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:290. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0118] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:291; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:292. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0119] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:293; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:284. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0120] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:295; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:296. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0121] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:297; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:298. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0122] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:299; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:300. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0123] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:301; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:302. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0124] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:303; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:304. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0125] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:305; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:306. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0126] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:307; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:308. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0127] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:309; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:310. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0128] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:311; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:312. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0129] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:313; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:314. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0130] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:315; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:316. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0131] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:317; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:318. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0132] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:319; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:320. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0133] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:321; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:322. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0134] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:323; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:324. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0135] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:325; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:326. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0136] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:327; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:328. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0137] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:329; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:330. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0138] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:331; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:332. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0139] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:333; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:334. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0140] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:335; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:336. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0141] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:337; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:338. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0142] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:339; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:340. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0143] In various embodiments, the FAP antigen-binding protein comprises a VH comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% identical to the three heavy chain CDRs in SEQ ID NO:341; and a VL comprising three CDRs that in combination are at least 85%, at least 90%, or at least 95% to the three light chain CDRs in SEQ ID NO:342. The antigen- binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0144] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 197, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 198.

[0145] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 199, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 200.

[0146] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 201, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 202.

[0147] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 203, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 204.

[0148] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 205, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 206.

[0149] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 207, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 208.

[0150] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 209, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 210.

[0151] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 211, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 212.

[0152] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 213, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 214.

[0153] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 215, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 216.

[0154] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 217, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 218.

[0155] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 219, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 220.

[0156] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 221, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 222.

[0157] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 223, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 224.

[0158] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 225, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 226.

[0159] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 227, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 228.

[0160] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 229, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 230.

[0161] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 231, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 232.

[0162] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 233, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 234.

[0163] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 235, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 236.

[0164] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 237, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 238.

[0165] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 239, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 240.

[0166] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 241, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 242.

[0167] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 243, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 244.

[0168] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 245, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 246.

[0169] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 247, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 248.

[0170] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 249, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 250.

[0171] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 251, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 252.

[0172] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 253, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 254.

[0173] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 255, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 256.

[0174] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 257, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 258.

[0175] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 259, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 260.

[0176] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 261, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 262.

[0177] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 263, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 264.

[0178] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 265, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 266.

[0179] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 267, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 268.

[0180] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 269, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 270.

[0181] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 271, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 272.

[0182] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 273, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 274.

[0183] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 275, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 276.

[0184] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 277, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 278.

[0185] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 279, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 280.

[0186] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 281, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 282.

[0187] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO:283, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 284.

[0188] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 285, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 286.

[0189] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 287, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 288.

[0190] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 289, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 290.

[0191] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 291, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 292.

[0192] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 293, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 294.

[0193] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 295, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 296.

[0194] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 297, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 298.

[0195] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 299, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 300.

[0196] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 301, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 302.

[0197] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 303, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 304.

[0198] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 305, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 306.

[0199] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 307, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 308.

[0200] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 309, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 310.

[0201] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 311, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 312.

[0202] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 313, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 314.

[0203] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 315, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 316.

[0204] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 317, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 318.

[0205] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 319, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 320.

[0206] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 321, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 322.

[0207] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 323, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 324.

[0208] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 325, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 326.

[0209] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 327, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 328.

[0210] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 329, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 330.

[0211] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 331, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 332.

[0212] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 333, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 334.

[0213] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 335, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 336.

[0214] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 337, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 338.

[0215] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 339, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 340.

[0216] In some embodiments, the FAP antigen-binding protein disclosed herein comprises: (i) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 341, and (ii) the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 342.

[0217] In exemplary aspects, the FAP antigen-binding proteins comprise (a) CDR-H1 amino acid sequence set forth in Sequence Table A, Tables 10F, 11F, 12F, and 13F, or a variant sequence thereof which differs by only 1-4 amino acids (e.g., 1, 2, 3, 4 amino acids) or which has at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity; (b) CDR-H2 amino acid sequence set forth in Sequence Table A, Tables 10F, 11F, 12F, and 13F, or a variant sequence thereof which differs by only 1-4 amino acids (e.g., 1, 2, 3, 4 amino acids) or which has at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity; (c) a CDR-H3 amino acid sequence set forth in Sequence Table A, Tables 10F, 11F, 12F, and 13F, or a variant sequence thereof which differs by only 1-4 amino acids (e.g., 1, 2, 3, 4 amino acids) or which has at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity; (d) a CDR-L1 amino acid sequence set forth in Sequence Table A, Tables 10F, 11F, 12F, and 13F, or a variant sequence thereof which differs by only 1-4 amino acids (e.g., 1, 2, 3, 4 amino acids) or which has at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity; (e) a CDR-L2 amino acid sequence set forth in Sequence Table A, Tables 10F, 11F, 12F, and 13F, or a variant sequence thereof which differs by only 1-4 amino acids (e.g., 1, 2, 3, 4 amino acids) or which has at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity; (f) a CDR-L3 amino acid sequence set forth in Sequence Table A, Tables 10F, 11F, 12F, and 13F, or a variant sequence thereof which differs by only 1-4 amino acids (e.g., 1, 2, 3, 4 amino acids) or which has at least about 80%, at least about 85%, at least about 90%, or at least about 95% sequence identity; or (g) a combination of any two, three, four, five, or six of (a)- (f). The antigen-binding protein may further bind to its target (FAP) with a KD value of 100 nM or less, or a KD value of 50 nM or less.

[0218] In exemplary embodiments, the FAP antigen-binding protein comprises 3, 4, 5, or all 6 of the amino acid sequences designated by the SEQ ID NOs under the same clone name in Sequence Table A, Tables 10F, 11F, 12F, and 13F. In exemplary embodiments, the antigen-binding protein comprises each of the LC CDR amino acid sequences designated by the SEQ ID NOs under the same clone name in Sequence Table A, Tables 10F, 11F, 12F, and 13F, and at least 1 or 2 of the HC CDR amino acid sequences designated by the SEQ ID NOs in under the same clone name of Sequence Table A, Tables 10F, 11F, 12F, and 13F. In exemplary embodiments, the FAP antigen- binding protein comprises each of the HC CDR amino acid sequences designated by the SEQ ID NOs under the same clone name in Sequence Table A, Tables 10F, 11F, 12F, and 13F, and at least 1 or 2 of the LC CDR amino acid sequences designated by the SEQ ID NOs under the same clone name in Sequence Table A, Tables 10F, 11F, 12F, and 13F. In exemplary embodiments, the antigen-binding protein comprises six CDR amino acid sequences listed under the same clone name in Sequence Table A, Tables 10F, 11F, 12F, and 13F, or comprising six CDR amino acid sequences selected from the group consisting of: (1) SEQ ID NOs: 1-6, (2) SEQ ID NOs: 7-12, (3) SEQ ID NOs: 13-18, (4) SEQ ID NOs: 19-24, (5) SEQ ID NOs: 25-30, (6) SEQ ID NOs: 31-36, (7) SEQ ID NOs: 37-42, (8) SEQ ID NOs: 43-48, (9) SEQ ID NOs: 49-54, (10) SEQ ID NOs: 55-60, (11) SEQ ID NOs: 61-66, (12) SEQ ID NOs: 67-72, (13) SEQ ID NOs: 73-78, (14) SEQ ID NOs: 79-84, (15) SEQ ID NOs: 85-90, (16) SEQ ID NOs: 91-96, (17) SEQ ID NOs: 97-102, (18) SEQ ID NOs: 103-108, (19) SEQ ID NOs: 109-114, (20) SEQ ID NOs: 115-120, (21) SEQ ID NOs: 121-126, (22) SEQ ID NOs: 127-132, (23) SEQ ID NOs: 133-138, (24) SEQ ID NOs: 139-144, (25) SEQ ID NOs: 145-150, (26) SEQ ID NOs: 151-156, (27) SEQ ID NOs: 157-162, (28) SEQ ID NOs: 163-168, (29) SEQ ID NOs: 169-174, (30) SEQ ID NOs: 175-180, (31) SEQ ID NOs: 181-186, (32) SEQ ID NOs: 187-192, (33) SEQ ID NOs: 43-47 and 193, (34) SEQ ID NOs: 43, 44, 194, 46, 47, and 193, (35) SEQ ID NOs: 175-179 and 195, and (36) SEQ ID NOs: 187, 188, 196, 190, 191, and 192.

[0219] In exemplary embodiments, the FAP antigen-binding protein comprises: a VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 398-402; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 403-407; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 408-412; and a VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 413-417; (ii) a CDR-L2 comprising any one of SEQ ID NOs: 418-422; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 423-427.

[0220] In exemplary embodiments, the FAP antigen-binding protein comprises: a VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 428-432; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 433-437; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 438-442; and a VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 443-447; (ii) a CDR-L2 comprising any one of SEQ ID NOs: 448-452; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 453-457.

[0221] In exemplary embodiments, the FAP antigen-binding protein comprises: a VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 458-462; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 463-467; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 468-472; and a VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 473-477; (ii) a CDR-L2 comprising any one of SEQ ID NOs: 478-482; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 483-487.

[0222] In exemplary embodiments, the FAP antigen-binding protein comprises: a VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 488-492; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 493-497; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 498-502; and a VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 503-507; (ii) a CDR-L2 comprising any one of SEQ ID NOs: 508-512; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 513-517.

[0223] In general, CDRs are separated by “framework” (FR) residues. A VH or VL domain framework comprises four framework sub-regions, FR1, FR2, FR3 and FR4, interspersed with CDRs in the following structure: FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. Accordingly, the antigen-binding proteins described herein may comprise a VH framework, such as a human germline VH framework sequence, and a VL framework, such as human germline VL framework sequences.

[0224] Preferred human germline light chain frameworks are frameworks derived from V ^ or V ^ germlines. It will be understood that if a sequence is “derived from” one or more germlines, what is referred to is a structural relationship, in which the features of a sequence correspond to the noted germline sequences, but may comprise somatic mutations or other amino acid differences relative to the noted germline sequence. For a sequence to be “derived from” a germline, an actual process of deriving that sequence from a germline sequence (either via molecular biology or computational analysis) is not necessarily required. For example, VL frameworks may be derived from one of the framework of the following germlines: DPK9 (IMGT name: IGKV1-39), DPK12 (IMGT name: IGKV2D- 29), DPK18 (IMGT name: IGKV2-30), DPK24 (IMGT name: IGKV4-1), HK102_V1 (IMGT name: IGKV1-5), DPK1 (IMGT name: IGKV1-33), DPK8 (IMGT name: IGKV1-9), DPK3 (IMGT name: IGKV1-6), DPK21 (IMGT name: IGKV3-15), Vg_38K (IMGT name: IGKV3-11 ), DPK22 (IMGT name: IGKV3-20), DPK15 (IMGT name: IGKV2-28), DPL16 (IMGT name: IGLV3-19), DPL8 (IMGT name: IGLV1-40), V1-22 (IMGT name: IGLV6-57). Alternatively, or in addition, the framework sequence may be derived from a human germline consensus framework sequence, such as the framework of human V ^1 consensus sequence, V ^3 consensus sequence, V ^1 consensus sequence, V ^2 consensus sequence, V ^3 consensus sequence. Sequences of human germline frameworks are available from various public databases, such as V-base, IMGT, NCBI, or Abysis.

[0225] The FAP antigen-binding proteins described herein may comprise a VL framework, wherein the framework may comprise one or more amino acid substitutions, additions, or deletions, while still retaining functional and structural similarity with the germline from which it was derived. In some aspects, the VL framework is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a human germline VL framework sequence. In some aspects, the antigen-binding protein, antibody, or antigen-binding fragment thereof, comprises a VL framework comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions relative to the human germline VL framework sequence.

[0226] The VH framework sequence can be derived from a human VH3 germline, a VH1 germline, a VH5 germline, a human VH2 germline, or a VH4 germline. Preferred human germline heavy chain frameworks are frameworks derived from VH1, VH3, or VH5 germlines. For example, VH frameworks may be derived from the framework of one of the following germlines: DP54 or IGHV3-7, DP47 or IGHV3-23, DP71 or IGHV4-59, DP75 or IGHV1-2_02, DP10 or IGHV1-69, DP7 or IGHV1-46, DP49 or IGHV3-30, DP51 or IGHV3-48, DP38 or IGHV3-15, DP79 or IGHV4-39, DP78 or IGHV4-30-4, DP73 or IGHV5-51, DP50 or IGHV3-33, DP46 or IGHV3-30-3, DP31 or IGHV3-9. Alternatively, or in addition, the framework sequence may be derived from the framework of a consensus sequence, such as: VH3 germline consensus sequence, VH1 germline consensus sequence, VH5 germline consensus sequence, VH2 germline consensus sequence, or VH4 germline consensus sequence.

[0227] The antigen-binding proteins described herein may comprise a VH framework, wherein the framework may comprise one or more amino acid substitutions, additions, or deletions, while still retaining functional and structural similarity with the germline from which it was derived. In some aspects, the VH framework is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a human germline VH framework sequence. In some aspects, the antigen-binding protein, antibody, or antigen-binding fragment thereof, comprises a VH framework comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions relative to the human germline VH framework sequence.

[0228] In exemplary embodiments, the FAP antigen-binding protein comprises a VH that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 197, 199, 202, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327,329, 331, 332, 334, 335, 339, or 341. In exemplary embodiments, the FAP antigen-binding protein comprises a VL that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 333, 336, 337, 338, 340, or 342. Preferably, the FAP antigen-binding protein comprises a pair of VH and VL sequences listed under the same clone name in Table B.

[0229] In some embodiments, the FAP antigen-binding protein comprises a CH1 domain, preferably a human CH1 domain (such as a human IgG1 CH1, a human IgG2 CH1, a human IgG3 CH1, or a human IgG4 CH1). Non-limiting examples of human CH1 sequences are provided in the Sequence Tables. In some embodiments, the CH1 domain comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 347, 364, 368, or 372.

[0230] In certain embodiments, the FAP antigen-binding proteins described herein comprises an Fc domain. The Fc domain can be derived from IgA (e.g., IgA1 or lgA2), IgG, IgE, or IgG (e.g., IgG1, lgG2, lgG3, or lgG4). In some embodiments, the Fc domain comprises wild type sequence of an Fc domain. Non-limiting examples of human Fc sequences are provided in the Sequence Table.

[0231] In some embodiments, the Fc domain comprises one or more mutations resulting in altered biological activity, such as to improve half-life / stability or to render the antibody more suitable for expression / manufacturability. For example, mutations may be introduced into the Fc domain to reduce the effector activity (e.g., WO 2005 / 063815), and / or to increase the homogeneity during the production of the recombinant protein.

[0232] In general, amino acid residues in the IgG heavy constant domain of an antibody are numbered according the EU index of Edelman et al., 1969, Proc. Natl. Acad. Sci. USA 63(1):78-85 as described in Kabat et al., 1991, referred to herein as the “EU index numbering.” Typically, the constant domain comprises from residue 118 to 447, and the Fc domain comprises from residue 236 to 447 of the human lgG1 constant domain. Comparison between EU numbering and other numbering systems can be found, e.g., at IGMT database.

[0233] Amino acid residues of the light chain constant domain are numbered according to Kabat et al., 1991, "Sequences of Proteins of Immunological Interest 5th Ed.", 1991, NATIONAL INSTITUTES OF HEALTH. Kappa light chain also has EU index numbering, and the EU index and Kabat numbering are identical. Lambda light chain does not have EU index numbering.

[0234] In some embodiments, the Fc domain is the Fc domain of human lgG1 and comprises one or more of the following effector-null mutations: L234A, L235A, and G237A (numbering according to the EU index), often referred as “LALA” mutations.

[0235] It has been reported that a single mutation of L235E was sufficient for knocking out binding to Fc receptors on U937 cells. Furthermore, the 100-fold reduction in binding to Fc ^R also resulted in lower T cell activation and proliferation in the presence of the L235E Fc mutant IgG1. Building upon this initial mutation it was found that the combination of L234A and L235A (commonly called LALA mutations) eliminated Fc ^RIIa binding. These two mutations were later shown to eliminate detectable binding to Fc ^RI, IIa, and IIIa for both IgG1 and IgG4. Other sites have been reported to knockout Fc receptor binding, such as Gly237Ala, Glu318Ala, Asp265Ala and Glu233Pro mutations.

[0236] In exemplary embodiments, the Fc region comprises a Stable Effector Functionless (SEFL) mutation to reduce the ability to interact with Fc ^ receptors. SEFL mutations are known in the art. See, e.g., Liu et al., J Biol Chem 292: 1876-1883 (2016); and Jacobsen et al., J. Biol. Chem.292: 1865- 1875 (2017). Further, US US9546203 discloses a Fc region comprising a N297G mutation, and one or more substitutions at position V259, A287, R292, V302, L306, V323, or I332, using EU numbering scheme, with a cysteine amino acid residue. In exemplary aspects, the SEFL mutation comprises one or more of the following mutations, numbered according to the EU system: L242C, A287C, R292C, N297G, V302C, L306C, and / or K334C. In exemplary aspects, the SEFL mutation comprises N297G. In exemplary aspects, the SEFL mutation comprises A287C, N297G, and L306C. In other exemplary aspects, the SEFL mutation comprises R292C, N297G, and V302C (i.e., SEFL2-2).

[0237] In exemplary embodiments, the Fc region comprises a YTE mutation. The M252Y / S254T / T256E (EU index numbering, referred to “YTE”) triple mutation have been shown to increase IgG half-life in cynomolgus monkeys by an approximate 4-fold increase.

[0238] C-terminal lysine clipping is a common phenomenon occurring during the bioproduction of monoclonal antibodies. Often, the lysine residue is removed via carboxypeptidase D (CpD), which results in generation of a mixture of antibody isoforms bearing zero or one C-terminal lysine residues on each heavy chain. Further, following C-terminal lysine cleavage, peptidylglycine ^-amidating monooxygenase (PAM) catalyzes the hydroxylation of glycine and removal of the glyoxylate from the glycine residue, leaving an amidated C-terminal proline. Therefore, during recombinant production of a monoclonal antibody, the product is often a mixture of C-terminal processing variants, with heavy chain C-terminus ends at (amidated) proline, glycine, or lysine. Sometimes, it may be desirable to delete the C-terminal lysine of the Fc domain to increase the homogeneity during the production of the recombinant protein.

[0239] In some embodiments, the terminal lysine may be absent; in some embodiments, the terminal lysine may be present; in some embodiments, the terminal glycine-lysine may be absent; in some embodiments, the terminal glycine-lysine may be present.

[0240] In exemplary embodiments, the FAP antigen-binding proteins described herein comprise Fc that is derived from an IgG1. In some embodiments, the Fc comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 348, 355, 356, 357, 358, 359, 360, 366, 370, or 374.

[0241] In exemplary embodiments, the FAP antigen-binding proteins described herein comprise an IgG1 heavy chain constant domain. In some embodiments, the heavy chain constant domain comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 90%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 349, 350, 351, 352, 353, 354, 361, 362, 363, 367, 371, or 375.

[0242] In some embodiments, the FAP antigen-binding protein described herein comprising a kappa or lambda light chain constant domain. In some embodiments, the kappa light chain constant domain comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:343 or 344. In some embodiments, the lambda light chain constant domain comprises a sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:345 or 346.

[0243] The FAP antigen-binding protein may be a full-length immunoglobulin, a Fab, or an scFv. The scFv may comprises a linker between VH and VL. Exemplary linker sequences, such as GS-based linkers, are provided in the Sequence Tables. 2.4 FAP-targeting Bispecific Molecules.

[0244] In various aspects, the antigen-binding protein is a bispecific molecule which binds to two different antigens or targets. In various instances, the bispecific molecule binds to both FAP and a T cell co-stimulatory molecule. In exemplary aspects, the bispecific molecule comprises 4 antigen- binding sites, 2 of which bind to FAP protein and 2 of which bind to the T cell co-stimulatory molecule. Optionally, each FAP binding site is identical to the other.

[0245] In one particular example, the bispecific molecule comprises an IgG moiety and an scFv moiety. As shown in FIG.5, there are two Fab moieties that bind to one antigen (e.g., a T cell co- stimulatory molecule). Each Fab moiety comprises two chains: a heavy chain comprising a heavy chain variable domain A (VHA) and a CH1 domain, and a light chain comprising a light chain variable domain A (VLA) and a CL domain. Each Fab is connected to one chain of Fc (CH2-CH3) to form an IgG. Because this part of the structure is essentially an IgG, there is no new linker between Fab and Fc (Fab and Fc are connected through “hinge” sequence just like a wildtype IgG). In addition, there are two scFv moieties that bind to the other antigen (e.g., FAP). Each scFv comprises a heavy chain variable domain B (VHB) and a light chain variable domain B (VLB); and the VHBand VLBare connected via a first linker. A second linker then connects the C-terminus of one CH3 domain to the N-terminus of one scFv. This particular structure is sometimes referred to as “IgG-scFv” format (one or more scFv moieties attached to an IgG molecule). Because each target has two binding domains, the bispecific molecule exemplified in FIG.5 is often referred herein to as “bivalent” bispecific molecules; nonetheless, it should be noted that it is also acceptable in the art to refer to such kind of molecule as “tetravalent,” as altogether there are four binding domains.

[0246] It is believed that, as compared to monovalent binding of FAP (e.g., a hetero-Ig molecule in which one arm of the antibody binds to a T-cell co-stimulatory molecule and one arm of the antibody binds to FAP), bivalent binding of FAP can enhance the crosslinking (clustering) of T-cell co- stimulatory molecules and potentially enhance the overall potency of the molecule.

[0247] A “linker” is a molecule or group of molecules that connects two separate entities to one another and can provide spacing and flexibility between the two entities such that they are able to achieve a conformation in which they, e.g., specifically bind their respective. Protein linkers are particularly preferred, and they may be expressed as a component of the recombinant protein using standard recombinant DNA techniques well-known in the art. For recombinant proteins described herein comprising two or more linkers (for example IgG-scFv format), the linkers may all be the same, or some or all of the linkers may be different from each other.

[0248] In some embodiments, the linker is a peptidyl linker. In some embodiments, the peptidyl linker comprises about 1 to 30 amino acid residues. Exemplary linkers include, e.g., a glycine rich peptide; a peptide comprising glycine and serine; a peptide having a sequence [Gly-Gly-Ser]n (SEQ ID NO:388), wherein n is 1, 2, 3, 4, 5, or 6; or a peptide having a sequence [Gly-Gly-Gly-Gly-Ser]n (SEQ ID NO: 387), wherein n is 1, 2, 3, 4, 5, or 6. A glycine rich peptide linker comprises a peptide linker, wherein at least 25% of the residues are glycine. Glycine rich peptide linkers are well known in the art (e.g., Chichili et al. Protein Sci.2013 February; 22(2): 153-167). The peptidyl linker may also be a proline- threonine rich peptide linker.

[0249] As shown in FIG.5, when bispecific molecule comprises a scFv moiety, mutations may be introduced to scFv to further improve stability. For example, it has been reported that insufficient interface stability between the heavy and light chains of scFv fragments could be the main cause of irreversible scFv inactivation. Fv fragments have been reported to dissociate into heavy-chain variable domains (VH) and light-chain variable domains (VL) with KD values ranging from 10−9to 10−6M. An interdomain disulfide bond have been used to further improve scFv stability. For example, mutation to Cys at the site of H44 (Kabat numbering), and mutation to Cys at L100 (Kabat numbering) would not significantly affect the domain folding. The two cysteines can then form an intramolecular disulfide bond to further stabilize the scFv. Such mutation is sometimes referred to as “cysteine clamp.”

[0250] Specific examples of scFv comprising cysteine clamps are shown in Sequence Table B, where mutations at H44 (Kabat numbering) and at L100 (Kabat numbering) were used to create disulfide bonds (referred to as “C-C”).

[0251] In exemplary embodiments, the scFv moiety that binds to FAP and comprises an amino acid sequence at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:393, 518, 519, 520, or 521.

[0252] The bispecific molecule disclosed herein may further comprises a CL, a CH1, and / or a Fc region as described in detail above. 2.5 Binding Characteristics

[0253] The antigen-binding proteins provided herein bind to their respective targets or antigens in a non-covalent and reversible manner. In exemplary embodiments, the binding strength of the antigen- binding proteins to their targets or antigens (e.g., FAP) may be described in terms of its affinity, a measure of the strength of interaction between the binding site of the antigen-binding protein and the target or antigen (e.g., FAP). In exemplary aspects, the antigen-binding proteins provided herein have high-affinity for their target or antigen (e.g., FAP) and thus will bind a greater amount of the target or antigen (e.g., FAP) in a shorter period of time than low-affinity antigen-binding proteins. In exemplary aspects, the antigen-binding proteins provided herein have low-affinity for FAP and thus will bind a lesser amount of FAP in a longer period of time than high-affinity antigen-binding proteins. In exemplary aspects, the antigen-binding protein has an equilibrium association constant, KA, which is at least 105M-1, at least 106M-1, at least 107M-1, at least 108M-1, at least 109M-1, at least 1010M-1, at least 1011M-1, at least 1012M-1, at least 1013M-1, or at least 1014M-1. As understood by the artisan of ordinary skill, KA can be influenced by factors including pH, temperature and buffer composition.

[0254] In exemplary embodiments, the binding strength of the antigen-binding protein to its target or antigen (e.g., FAP) may be described in terms of its sensitivity. KDis the equilibrium dissociation constant, a ratio of koff / kon, between the antigen-binding protein and its target or antigen (e.g., FAP). KD and KA are inversely related. The KD value relates to the concentration of the antigen-binding protein (the amount of antigen-binding protein needed for a particular experiment) and so the lower the KDvalue (lower concentration needed) the higher the affinity of the antigen-binding protein. In exemplary aspects, the binding strength of the antigen-binding protein to its target (e.g., FAP) may be described in terms of KD. In exemplary aspects, the KD value of the antigen-binding proteins provided herein is about 10-1M or less, about 10-2M or less, about 10-3M or less, about 10-4M or less, about 10-5M or less, about 10-6M or less, about 10-7M or less, about 10-8M or less, about 10-9M or less, about 10-10M or less, about 10-11M or less, about 10-12M or less, about 10-13M or less, about 10-14M or less, from about 10-5M to about 10-15M, from about 10-6M to about 10-15M, from about 10-7M to about 10-15M, from about 10-8M to about 10-15M, from about 10-9M to about 10-15M, from about 10-10M to about 10-15M, from about 10-5M to about 10-14M, from about 10-6M to about 10-14M, from about 10-7M to about 10-14M, from about 10-8M to about 10-14M, from about 10-9M to about 10-14M, from about 10-10M to about 10-14M, from about 10-5M to about 10-13M, from about 10-6M to about 10-13M, from about 10-7M to about 10-13M, from about 10-8M to about 10-13M, from about 10-9M to about 10-13M, or from about 10-10M to about 10-13M.

[0255] In exemplary aspects, the KDof the antigen-binding proteins provided herein is micromolar, nanomolar, picomolar or femtomolar. In exemplary aspects, the KD of the antigen-binding proteins provided herein is within a range of about 10-4to 10-6M, or 10-7to 10-9M, or 10-10to 10-12M, or 10-13to 10-15M. In exemplary aspects, the antigen-binding protein binds to the human FAP with a KD value that is from about 0.07 nM to about 4 nM. In exemplary aspects, the antigen-binding protein binds to the human FAP with a KD of from about 0.01 nM to about 50 nM, from about 0.02 nM to about 50 nM, from about 0.05 nM to about 50 nM, from about 0.05 nM to about 45 nM, from 0.05 nM to about 40 nM, from about 0.05 nM to about 35 nM, from about 0.05 nM to about 30 nM, from about 0.05 nM to about 25 nM, from about 0.05 nM to about 20 nM, from about 0.05 nM to about 15 nM, or from about 0.05 nM to about 10 nM. In exemplary aspects, the antigen-binding protein binds to the cynomolgus monkey FAP with a KDthat is from about 0.05 nM to about 4 nM. In exemplary aspects, the antigen- binding protein binds to the cynomolgus monkey FAP with a KDof from about 0.01 nM to about 50 nM, from about 0.02 nM to about 50 nM, from about 0.05 nM to about 50 nM, from about 0.05 nM to about 45 nM, from 0.05 nM to about 40 nM, from about 0.05 nM to about 35 nM, from about 0.05 nM to about 30 nM, from about 0.05 nM to about 25 nM, from about 0.05 nM to about 20 nM, from about 0.05 nM to about 15 nM, or from about 0.05 nM to about 10 nM. In exemplary embodiments, the FAP antigen-binding protein binds to human FAP with a KDvalue of from about 0.05 nM to about 5 nM. In exemplary embodiments, the FAP antigen-binding protein binds to cynomolgus monkey FAP with a KD value of from about 0.05 nM to about 5 nM.

[0256] KDvalues can be determined using methods well established in the art. One exemplary method for measuring KD is surface plasmon resonance (SPR), a method well-known in the art (e.g., Nguyen et al. Sensors (Basel).2015 May 5; 15(5):10481-510). KD value may be measured by SPR using a biosensor system such as a BIACORE® system. BIAcore kinetic analysis comprises analyzing the binding and dissociation of an antigen from chips with immobilized molecules (e.g. molecules comprising epitope binding domains), on their surface. Another well-known method in the art for determining the KD of a protein is by using Bio-Layer Interferometry (e.g., Shah et al. J Vis Exp.2014; (84): 51383). KD value may be measured by Bio-Layer Interferometry using OCTET® technology (Octet QKe system, ForteBio). Alternatively or in addition, a KinExA® (Kinetic Exclusion Assay) assay, available from Sapidyne Instruments (Boise, Id.) can also be used. Any method known in the art for assessing the binding affinity between two binding partners is encompassed herein.

[0257] In some aspects, the KDvalue is measured by surface plasmon resonance (SPR). Antigen (e.g., FAP) may be immobilized, e.g., on a solid surface. The antigen may be immobilized to a chip, for example by covalent coupling (such as amine coupling). The chip may be a CM5 sensor chip. As the analyte binds to the ligand the accumulation of protein on the sensor surface causes an increase in refractive index. This refractive index change is measured in real time (sampling in a kinetic analysis experiment is taken every 0.1 s), and the result plotted as response units (RU) versus time (termed a sensorgram). A response (background response) will also be generated if there is a difference in the refractive indices of the running and sample buffers. This background response must be subtracted from the sensorgram to obtain the actual binding response. The background response is recorded by injecting the analyte through a control or reference flow cell, which has no ligand or an irrelevant ligand immobilized to the sensor surface. The real-time measurement of association and dissociation of a binding interaction allows for the calculation of association and dissociation rate constants and the corresponding affinity constants. One RU represents the binding of 1 pg of protein per square mm. More than 50 pg per square mm of analyte binding is generally needed in practice to generate good reproducible responses.

[0258] Dissociation of the antigen-binding protein from the antigen may be monitored for about 3600 seconds. The SPR analysis may be conducted, and the data collected at between about 15°C and about 37°C. The SPR analysis may be conducted, and the data collected at between about 25°C and 37°C. The SPR analysis may be conducted, and the data collected at about 37°C. The SPR analysis may be conducted, and the data collected at 37°C. The KDvalue may be measured by SPR using a BIAcore T200 instrument. The SPR rates and affinities may be determined by fitting resulting sensorgram data to a 1:1 model in BIAcore T200 Evaluation software version 1.0. The collection rate may be about 1 Hz.

[0259] Another method for determining the KDof an antibody is by using Bio-Layer Interferometry (BLI), typically using OCTET® technology (Octet QKe system, ForteBio). In some embodiments, biosensor analysis is used. Typically, one interactant is immobilized on the surface of the biosensor ("ligand," such as an antigen-binding protein) and the other remains in solution (“analyte”, such as an antigen). The assay begins with an initial baseline or equilibration step using assay buffer. Next, a ligand (such as an antigen-binding protein) is immobilized on the surface of the biosensor (loading), either by direct immobilization or capture-based method. After ligand immobilization, biosensors are dipped into buffer solution for a baseline step to assess assay drift and determine loading level of ligand. After the baseline step, biosensors are dipped into a solution containing the ligand's binding partner, the analyte (association). In this step, the binding interaction of the analyte to the immobilized ligand is measured. Following analyte association, the biosensor is dipped into buffer solution without analyte, and the bound analyte is allowed to come off the ligand (dissociation). The series of assay steps is then repeated on new or regenerated biosensors for each analyte being tested. Each binding response is measured and reported in real time on a sensorgram trace. The instrument may be Octet QKe system, Octet RED96 system, Octet QK384 system, or RED384 system.

[0260] In certain embodiments, the FAP binding protein binds human FAP with a KD value of or less than: about 200nM, about 150nM, about 100nM, about 90nM, about 80nM, about 70nM, about 60nM, about 50nM, about 40nM, about 30nM, about 25nM, about 20nM, about 15nM, about 10nM, about 9nM, about 8nM, about 7nM, about 6nM, about 5nM, about 4nM, about 3nM, about 2nM, about 1 nM, about 900pM, about 800pM, about 700pM, about 600pM, about 500pM, about 400pM, about 300pM, about 250pM, about 200pM, about 150pM, about 100pM, about 50pM, about 40pM, about 30pM, about 25pM, about 20pM, about 15pM, about 10pM, about 5pM, or about 1pM. KDvalue may be measured by surface plasmon resonance (SPR) (e.g., a Biacore T200 instrument); or it may be measured by bio-layer interferometry (BLI) (e.g., a ForteBio Octet instrument).

[0261] Exemplary method to measure binding of the antigen-binding protein to its target is also provided in Examples 1 and 2. 2.6 Cross-Reactivity

[0262] In various aspects, the antigen-binding protein binds to human FAP. A reference amino acid sequence of human FAP is provided herein as SEQ ID NO: 394 (the recombinantly expressed soluble FAP is provided as SEQ ID NO:395). In various aspects, the antigen-binding protein binds to cynomolgus monkey (cyno) FAP. The amino acid sequence of cyno FAP is provided herein as SEQ ID NO: 396. In exemplary aspects, the antigen-binding protein binds with high affinity to both human FAP and cyno FAP. In various embodiments, the antigen-binding proteins of the present disclosure bind to human FAP and cyno FAP but do not cross-react with any other FAP orthologs. In various instances, the antigen-binding protein binds with high affinity to both human FAP and cyno FAP and does not bind to any other FAP ortholog, e.g., does not bind to mouse FAP, rat FAP, canine FAP, bovine FAP, and the like. In various embodiments, the antigen-binding proteins of the present disclosure have a selectivity for human and cyno FAP which is at least 10-fold, 5-fold, 4-fold, 3-fold, 2- fold greater than the selectivity of the antigen-binding protein for any other FAP ortholog. In various embodiments, the antigen-binding proteins of the present disclosure have a KDfor human and cyno FAP which is at least 10-fold, 5-fold, 4-fold, 3-fold, 2-fold less than the KD of the antigen-binding protein for any other FAP ortholog. 2.7 Competition assays

[0263] In various embodiments, the antigen-binding protein inhibits a binding interaction between human FAP and a reference antibody, which reference antibody is known to bind to FAP. By way of example, the reference antibody may be a FAP antigen-binding protein disclosed herein, such as those disclosed in the Sequence Tables. In various instances, a FAP antigen-binding protein competes with the reference antibody for binding to human FAP and thereby reduce the amount of human FAP bound to the reference antibody as determined by an in vitro competitive binding assay. In various aspects, the FAP antigen-binding protein inhibits the binding interaction between human FAP and the reference antibody and the inhibition is characterized by an IC50. In various aspects, the FAP antigen-binding protein exhibits an IC50 of less than about 2500 nM for inhibiting the binding interaction between human FAP and the reference antibody. In various aspects, the antigen-binding proteins exhibit an IC50of less than about 2000 nM, less than about 1500 nM, less than about 1000 nM, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, or less than about 100 nm. In various aspects, the antigen-binding proteins exhibit an IC50 of less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, or less than about 10 nM. In various instances, the FAP antigen-binding protein competes with the reference antibody for binding to human FAP and thereby reduce the amount of human FAP bound to the reference antibody as determined by a FACS-based assay in which the fluorescence of a fluorophore- conjugated secondary antibody which binds to the Fc of the reference antibody is measured in the absence or presence of a particular amount of the FAP antigen-binding protein. In various aspects, the FACS-based assay is carried out with the reference antibody, fluorophore-conjugated secondary antibody and cells which express FAP. In various aspects, the cells are genetically-engineered to overexpress FAP. In some aspects, the cells are HEK293T cells transduced with a viral vector to express FAP. In alternative aspects, the cells endogenously express FAP. Before the FACS-based assay is carried out, in some aspects, the cells which endogenously express FAP are pre-determined as low FAP-expressing cells or high FAP-expressing cells.

[0264] Other binding assays, e.g., competitive binding assays or competition assays, which test the ability of one antigen-binding molecule (such as an antibody) to compete with a second antigen- binding molecule (such as a second antibody) for binding to an antigen, or to an epitope thereof, are known in the art. See, e.g., Trikha et al., Int J Cancer 110: 326-335 (2004); Tam et al., Circulation 98(11): 1085-1091 (1998). U.S. Patent Application Publication No. US20140178905, Chand et al., Biologicals 46: 168-171 (2017); Liu et al., Anal Biochem 525: 89-91 (2017); and Goolia et al., J Vet Diagn Invest 29(2): 250-253 (2017). Also, other methods of comparing two antigen-binding molecules are known in the art, and include, for example, surface plasmon resonance (SPR). SPR can be used to determine the binding constants of the two binding molecules, and the two binding constants can be compared. 3. Nucleic Acids, Vectors, and Host Cells 3.1 Nucleic acids

[0265] The present disclosure further provides nucleic acids comprising a nucleotide sequence encoding the antigen-binding proteins disclosed herein. The nucleic acid may comprise a single nucleic acid molecule, or two or more nucleic acid molecules (for example, a first nucleic acid molecule encoding a heavy chain amino acid sequence and a second nucleic acid molecule encoding a light chain amino acid sequence). In some aspects, the nucleic acids of the present disclosure are recombinant.

[0266] In addition, nucleic acid sequence that encoding a signal peptide may be added to the 5’ of the polypeptide disclosed herein. Recombinant expression of the antigen-binding proteins (or antigen- binding moieties) disclosed herein often require that the molecules be secreted. Translocation of a nascent protein from the cytosol into the ER mediated by its signal peptide is an important step in protein secretion. It is understood that the signal peptide is present (and often critical) during the initial synthesis of a nascent protein, but then, signal peptide is cleaved during secretion process. Therefore, while the mature protein no longer has the signal peptide; having the signal peptide coding sequence in the nucleic acid is generally necessary to recombinantly express the protein. 3.2 Vectors

[0267] The nucleic acids of the present disclosure in some aspects are incorporated into a vector. In this regard, the present disclosure provides vectors comprising any of the presently disclosed nucleic acids. In exemplary aspects, the vector is a recombinant expression vector. For purposes herein, the term "recombinant expression vector" means a genetically-modified oligonucleotide or polynucleotide construct that permits the expression of an mRNA, protein, polypeptide, or peptide by a host cell, when the construct comprises a nucleotide sequence encoding the mRNA, protein, polypeptide, or peptide, and the vector is contacted with the cell under conditions sufficient to have the mRNA, protein, polypeptide, or peptide expressed within the cell. The vectors of the present disclosure are not naturally-occurring as a whole. However, parts of the vectors can be naturally-occurring. The presently disclosed vectors can comprise any type of nucleotides, including, but not limited to DNA and RNA, which can be single- stranded or double-stranded, synthesized or obtained in part from natural sources, and which can contain natural, non-natural or altered nucleotides. The vectors can comprise naturally-occurring or non-naturally-occurring internucleotide linkages, or both types of linkages. In some aspects, the altered nucleotides or non-naturally occurring internucleotide linkages do not hinder the transcription or replication of the vector.

[0268] The vector of the present disclosure can be any suitable vector, and can be used to transform or transfect any suitable host. Suitable vectors include those designed for propagation and expansion or for expression or both, such as plasmids and viruses. The vector can be selected from the group consisting of the pUC series (Fermentas Life Sciences), the pBluescript series (Stratagene, LaJoIIa, CA), the pET series (Novagen, Madison, WI), the pGEX series (Pharmacia Biotech, Uppsala, Sweden), and the pEX series (Clontech, Palo Alto, CA). Bacteriophage vectors, such as ^GTIO, ^GTl 1, ^ZapII (Stratagene), ^EMBL4, and ^NMl 149, also can be used. Examples of plant expression vectors include pBI101, pBI101.2, pBI101.3, pBI121 and pBIN19 (Clontech). Examples of animal expression vectors include pEUK-Cl, pMAM and pMAMneo (Clontech). In some aspects, the vector is a viral vector, e.g., a retroviral vector.

[0269] The vectors of the present disclosure can be prepared using standard recombinant DNA techniques described in, for example, Sambrook et al., infra, and Ausubel et al., infra. Constructs of expression vectors, which are circular or linear, can be prepared to contain a replication system functional in a prokaryotic or eukaryotic host cell. Replication systems can be derived, e.g., from CoIEl, 2 μ plasmid, λ, SV40, bovine papilloma virus, and the like.

[0270] In some aspects, the vector comprises regulatory sequences, such as transcription and translation initiation and termination codons, which are specific to the type of host (e.g., bacterium, fungus, plant, or animal) into which the vector is to be introduced, as appropriate and taking into consideration whether the vector is DNA- or RNA- based.

[0271] The vector can include one or more marker genes, which allow for selection of transformed or transfected hosts. Marker genes include biocide resistance, e.g., resistance to antibiotics, heavy metals, etc., complementation in an auxotrophic host to provide prototrophy, and the like. Suitable marker genes for the presently disclosed expression vectors include, for instance, neomycin / G418 resistance genes, hygromycin resistance genes, histidinol resistance genes, tetracycline resistance genes, and ampicillin resistance genes.

[0272] The vector can comprise a native or normative promoter operably linked to the nucleotide sequence encoding the polypeptide (including functional portions and functional variants thereof), or to the nucleotide sequence which is complementary to or which hybridizes to the nucleotide sequence encoding the antigen-binding protein. The selection of promoters, e.g., strong, weak, inducible, tissue- specific and developmental- specific, is within the ordinary skill of the artisan. Similarly, the combining of a nucleotide sequence with a promoter is also within the skill of the artisan. The promoter can be a non-viral promoter or a viral promoter, e.g., a cytomegalovirus (CMV) promoter, an SV40 promoter, an RSV promoter, and a promoter found in the long-terminal repeat of the murine stem cell virus. 3.3 Host cells

[0273] Provided herein are host cells comprising a nucleic acid or vector of the present disclosure. As used herein, the term "host cell" refers to any type of cell that can contain the presently disclosed vector and is capable of producing an expression product encoded by the nucleic acid (e.g., mRNA, protein). The host cell in some aspects is an adherent cell or a suspended cell, i.e., a cell that grows in suspension. The host cell in exemplary aspects is a cultured cell or a primary cell, i.e., isolated directly from an organism, e.g., a human. The host cell can be of any cell type, can originate from any type of tissue, and can be of any developmental stage.

[0274] In exemplary aspects, the cell is a eukaryotic cell, including, but not limited to, a yeast cell, filamentous fungi cell, protozoa cell, algae cell, insect cell, or mammalian cell. Such host cells are described in the art. See, e.g., Frenzel, et al., Front Immunol 4: 217 (2013). In exemplary aspects, the eukaryotic cells are mammalian cells. In exemplary aspects, the mammalian cells are non-human mammalian cells. In some aspects, the cells are Chinese Hamster Ovary (CHO) cells and derivatives thereof (e.g., CHO-K1, CHO pro-3, CS9), mouse myeloma cells (e.g., NS0, GS-NS0, Sp2 / 0), cells engineered to be deficient in dihydrofolatereductase (DHFR) activity (e.g., DUKX-X11, DG44), human embryonic kidney 293 (HEK293) cells or derivatives thereof (e.g., HEK293T, HEK293-EBNA), green African monkey kidney cells (e.g., COS cells, VERO cells), human cervical cancer cells (e.g., HeLa), human bone osteosarcoma epithelial cells U2-OS, adenocarcinomic human alveolar basal epithelial cells A549, human fibrosarcoma cells HT1080, mouse brain tumor cells CAD, embryonic carcinoma cells P19, mouse embryo fibroblast cells NIH 3T3, mouse fibroblast cells L929, mouse neuroblastoma cells N2a, human breast cancer cells MCF-7, retinoblastoma cells Y79, human retinoblastoma cells SO-Rb50, human liver cancer cells Hep G2, mouse B myeloma cells J558L, or baby hamster kidney (BHK) cells (Gaillet et al.2007; Khan, Adv Pharm Bull 3(2): 257-263 (2013)). In a particular embodiment, the host cell is CS9 (a CHO cell line).

[0275] For purposes of amplifying or replicating the vector, the host cell is in some aspects is a prokaryotic cell, e.g., a bacterial cell.

[0276] Also provided by the present disclosure is a population of cells comprising at least one host cell described herein. The population of cells in some aspects is a heterogeneous population comprising the host cell comprising vectors described, in addition to at least one other cell, which does not comprise any of the vectors. Alternatively, in some aspects, the population of cells is a substantially homogeneous population, in which the population comprises mainly host cells (e.g., consisting essentially of) comprising the vector. The population in some aspects is a clonal population of cells, in which all cells of the population are clones of a single host cell comprising a vector, such that all cells of the population comprise the vector. In exemplary embodiments of the present disclosure, the population of cells is a clonal population comprising host cells comprising a vector as described herein. 3.4. Methods of Manufacture

[0277] The antigen-binding proteins disclosed herein may be obtained by methods known in the art. Suitable methods of de novo synthesizing polypeptides are described in, for example, Chan et al., Fmoc Solid Phase Peptide Synthesis, Oxford University Press, Oxford, United Kingdom, 2005; Peptide and Protein Drug Analysis, ed. Reid, R., Marcel Dekker, Inc., 2000; Epitope Mapping, ed. Westwood et al., Oxford University Press, Oxford, United Kingdom, 2000; and U.S. Patent No. 5,449,752. Additional exemplary methods of making the peptides of the invention are set forth herein.

[0278] Also, in some aspects, the antigen-binding proteins disclosed herein are recombinantly produced using a nucleic acid encoding the amino acid sequence of the molecule using standard recombinant methods. See, for instance, Sambrook et al., Molecular Cloning: A Laboratory Manual. 3rd ed., Cold Spring Harbor Press, Cold Spring Harbor, NY 2001; and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, NY, 1994.

[0279] Methods of making antigen-binding proteins disclosed herein are further provided herein. In exemplary embodiments, the method comprises culturing a presently disclosed host cell so as to express the antigen-binding protein and harvesting the expressed antigen-binding protein. The host cell can be any of the host cells described herein. In exemplary aspects, the host cell is selected from the group consisting of: CHO cells, NS0 cells, COS cells, VERO cells, and BHK cells. In exemplary aspects, the step of culturing a host cell comprises culturing the host cell in a growth medium to support the growth and expansion of the host cell. In exemplary aspects, the growth medium increases cell density, culture viability and productivity in a timely manner. In exemplary aspects, the growth medium comprises amino acids, vitamins, inorganic salts, glucose, and serum as a source of growth factors, hormones, and attachment factors. In exemplary aspects, the growth medium is a fully chemically defined media consisting of amino acids, vitamins, trace elements, inorganic salts, lipids and insulin or insulin-like growth factors. In addition to nutrients, the growth medium also helps maintain pH and osmolality. Several growth media are commercially available and are described in the art. See, e.g., Arora, “Cell Culture Media: A Review” MATER METHODS 3:175 (2013).

[0280] In exemplary aspects, the method of making antigen-binding proteins disclosed herein comprises culturing the host cell in a feed medium. In exemplary aspects, the method comprises culturing in a feed medium in a fed-batch mode. Methods of recombinant protein production are known in the art. See, e.g., Li et al., “Cell culture processes for monoclonal antibody production” MAbs 2(5): 466–477 (2010).

[0281] The method of making antigen-binding proteins disclosed herein can comprise one or more steps for purifying the molecule from a cell culture or the supernatant thereof and preferably recovering the purified protein. In exemplary aspects, the method comprises one or more chromatography steps, e.g., affinity chromatography (e.g., protein A affinity chromatography), ion exchange chromatography, hydrophobic interaction chromatography. In exemplary aspects, the method comprises purifying the protein using a Protein A affinity chromatography resin.

[0282] In exemplary embodiments, the method further comprises steps for formulating the purified protein, etc., thereby obtaining a formulation comprising the purified protein. Such steps are described, for example, in Formulation and Process Development Strategies for Manufacturing, eds. Jameel and Hershenson, John Wiley & Sons, Inc. (Hoboken, NJ), 2010. 4. Pharmaceutical Compositions and Method of Treatment 4.1 Pharmaceutical Compositions

[0283] Compositions comprising an antigen-binding protein, a nucleic acid, a vector, a host cell, or a combination thereof, are provided herein. The compositions may comprise the antigen-binding protein, nucleic acid, vector, or host cell, or a combination thereof, in isolated and / or purified form.

[0284] In exemplary aspects, the composition comprises agents which enhance the chemico-physico features of the antigen-binding molecule, nucleic acid, vector, or host cell, or a combination thereof, e.g., via stabilizing, for example, at certain temperatures (e.g., room temperature), increasing shelf life, reducing degradation, e.g., oxidation protease mediated degradation, increasing half-life of the antigen-binding protein, etc.

[0285] In exemplary aspects of the present disclosure, the composition additionally comprises a pharmaceutically acceptable carrier, diluents, or excipient. The pharmaceutical composition can comprise any pharmaceutically acceptable ingredients, including, for example, acidifying agents, additives, adsorbents, aerosol propellants, air displacement agents, alkalizing agents, anticaking agents, anticoagulants, antimicrobial preservatives, antioxidants, antiseptics, bases, binders, buffering agents, chelating agents, coating agents, coloring agents, desiccants, detergents, diluents, disinfectants, disintegrants, dispersing agents, dissolution enhancing agents, dyes, emollients, emulsifying agents, emulsion stabilizers, fillers, film forming agents, flavor enhancers, flavoring agents, flow enhancers, gelling agents, granulating agents, humectants, lubricants, mucoadhesives, ointment bases, ointments, oleaginous vehicles, organic bases, pastille bases, pigments, plasticizers, polishing agents, preservatives, sequestering agents, skin penetrants, solubilizing agents, solvents, stabilizing agents, suppository bases, surface active agents, surfactants, suspending agents, sweetening agents, therapeutic agents, thickening agents, tonicity agents, toxicity agents, viscosity- increasing agents, water-absorbing agents, water-miscible cosolvents, water softeners, or wetting agents. See, e.g., the Handbook of Pharmaceutical Excipients, Third Edition, A. H. Kibbe (Pharmaceutical Press, London, UK, 2000), which is incorporated by reference in its entirety. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), which is incorporated by reference in its entirety.

[0286] In exemplary aspects, the pharmaceutical composition comprises formulation materials that are nontoxic to recipients at the dosages and concentrations employed. In specific embodiments, pharmaceutical compositions comprising an active agent and one or more pharmaceutically acceptable salts; polyols; surfactants; osmotic balancing agents; tonicity agents; anti-oxidants; antibiotics; antimycotics; bulking agents; lyoprotectants; anti-foaming agents; chelating agents; preservatives; colorants; analgesics; or additional pharmaceutical agents. In exemplary aspects, the pharmaceutical composition comprises one or more polyols and / or one or more surfactants, optionally, in addition to one or more excipients, including but not limited to, pharmaceutically acceptable salts; osmotic balancing agents (tonicity agents); anti-oxidants; antibiotics; antimycotics; bulking agents; lyoprotectants; anti-foaming agents; chelating agents; preservatives; colorants; and analgesics.

[0287] In certain embodiments, the pharmaceutical composition can contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants. See, REMINGTON'S PHARMACEUTICAL SCIENCES, 18″ Edition, (A. R. Genrmo, ed.), 1990, Mack Publishing Company.

[0288] The pharmaceutical compositions can be formulated to achieve a physiologically compatible pH. In some embodiments, the pH of the pharmaceutical composition can be for example between about 4 or about 5 and about 8.0 or about 4.5 and about 7.5 or about 5.0 to about 7.5. In exemplary embodiments, the pH of the pharmaceutical composition is between 5.5 and 7.5. 4.2 Methods of Treatment

[0289] Methods of treatment are additionally provided by the present disclosure. The method, in exemplary embodiments, is a method of treating a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutical composition of the present disclosure in an amount effective to treat the subject.

[0290] Provided herein are methods of treating a subject with cancer and methods of treating a subject with a solid tumor. In exemplary embodiments, the method comprises administering to the subject the pharmaceutical composition of the present disclosure in an amount effective for treating the cancer or the solid tumor in the subject.

[0291] The cancer treatable by the methods disclosed herein can be any cancer, e.g., any malignant growth or tumor caused by abnormal and uncontrolled cell division that may spread to other parts of the body through the lymphatic system or the blood stream. The cancer in some aspects is one selected from the group consisting of acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, Hodgkin lymphoma, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharynx cancer, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, peritoneum, omentum, and mesentery cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer (e.g., renal cell carcinoma (RCC)), small intestine cancer, soft tissue cancer, stomach cancer, testicular cancer, thyroid cancer, ureter cancer, and urinary bladder cancer. In particular aspects, the cancer is selected from the group consisting of: head and neck, ovarian, cervical, bladder and oesophageal cancers, pancreatic, gastrointestinal cancer, gastric, breast, endometrial and colorectal cancers, hepatocellular carcinoma, glioblastoma, bladder, lung cancer, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma. In particular embodiments, the tumor is non-small cell lung cancer (NSCLC), head and neck cancer, renal cancer, triple negative breast cancer, and gastric cancer. In exemplary aspects, the subject has a tumor (e.g., a solid tumor, a hematological malignancy, or a lymphoid malignancy) and the pharmaceutical composition is administered to the subject in an amount effective to treat the tumor in the subject. In other exemplary aspects, the tumor is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), head and neck cancer, renal cancer, breast cancer, melanoma, ovarian cancer, liver cancer, pancreatic cancer, colon cancer, prostate cancer, gastric cancer, lymphoma or leukemia, and the pharmaceutical composition is administered to the subject in an amount effective to treat the tumor in the subject.

[0292] As used herein, the term “treat,” as well as words related thereto, do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the methods of treating cancer of the present disclosure can provide any amount or any level of treatment. Furthermore, the treatment provided by the method of the present disclosure can include treatment of one or more conditions or symptoms or signs of the cancer being treated. Also, the treatment provided by the methods of the present disclosure can encompass slowing the progression of the cancer. For example, the methods can treat cancer by virtue of enhancing the T cell activity or an immune response against the cancer, reducing tumor or cancer growth, reducing metastasis of tumor cells, increasing cell death of tumor or cancer cells, and the like. In exemplary aspects, the methods treat by way of delaying the onset or recurrence of the cancer by 1 day, 2 days, 4 days, 6 days, 8 days, 10 days, 15 days, 30 days, two months, 4 months, 6 months, 1 year, 2 years, 4 years, or more. In exemplary aspects, the methods treat by way increasing the survival of the subject.

[0293] In particular, the antigen-binding proteins disclosed herein target cancer-associated fibroblasts that is present in tumor stroma. Tumor stroma, broadly defined as the non-cancer cell and non- immune cell components of tumors, is viewed traditionally as the structural components holding tumor tissues together. Tumor stroma is composed of extracellular matrix and specialized connective tissue cells, including fibroblasts and mesenchymal stromal cells. Tumors generally need stroma for nutritional support and the removal of waste products, but stromal content can vary markedly in different types of cancers. For example, many lymphomas have minimal stroma whereas the stroma may make up 90% of other solid tumors. The antigen-binding proteins disclosed herein in particular target FAP+ tumors. Fibroblasts are capable of infiltrating tumors and FAP+ cells can be easily identified by methods well known in the art, such as immunostaining. 4.3 Subjects

[0294] In some embodiments of the present disclosure, the subject is a mammal, including, but not limited to, mammals of the order Rodentia, such as mice and hamsters, and mammals of the order Logomorpha, such as rabbits, mammals from the order Carnivora, including Felines (cats) and Canines (dogs), mammals from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). In some aspects, the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes). In some aspects, the mammal is a human. 5. Kits

[0295] The present disclosure additionally provides kits comprising an antigen-binding protein, nucleic acid, vector, or host cell of the present disclosure, or a combination thereof. In exemplary aspects, the antigen-binding protein, nucleic acid, vector, or host cell is provided in the kit as a unit dose. For purposes herein “unit dose" refers to a discrete amount dispersed in a suitable carrier. In exemplary aspects, the unit dose is the amount sufficient to provide a subject with a desired effect, e.g., treatment of cancer. In exemplary aspects, the kit comprises several unit doses, e.g., a week or month supply of unit doses, optionally, each of which is individually packaged or otherwise separated from other unit doses. In some embodiments, the components of the kit / unit dose are packaged with instructions for administration to a patient. In some embodiments, the kit comprises one or more devices for administration to a patient, e.g., a needle and syringe, and the like. In some aspects, the antigen-binding protein, nucleic acid, vector, host cell, or a combination thereof, is / are pre-packaged in a ready to use form, e.g., a syringe, an intravenous bag, etc. In exemplary aspects, the ready to use form is for a single use. In exemplary aspects, the kit comprises multiple single use, ready to use forms of the antigen-binding protein, nucleic acid, vector, or host cell of the present disclosure. In some aspects, the kit further comprises other therapeutic or diagnostic agents or pharmaceutically acceptable carriers (e.g., solvents, buffers, diluents, etc.), including any of those described herein.

[0296] The following examples are given merely to illustrate the present invention and not in any way to limit its scope. EXAMPLES EXAMPEL 1. Generation and characterization of anti-FAP antibodies 1. Anti-FAP antibody generation

[0297] Fully human antibodies to human FAP were generated by immunizing XENOMOUSE® transgenic mice (U.S. Pat. NOs.6,114,598; 6,162,963;6,833,268; 7,049,426; 7,064,244, which are incorporated herein by reference in their entirety; Green et al., 1994, Nature Genetics 7:13-21; Mendez et al., 1997, Nature Genetics 15:146-156; Green and Jakobovits, 1998, J. Ex. Med, 188:483- 495; Kellerman and Green, Current Opinion in Biotechnology 13, 593-597, 2002). Animals from the XMG4 and XMG2 XENOMOUSE® strains were used for these immunizations. Multiple immunogens and routes of immunization were used to generate anti-human FAP immune responses. For genetic immunizations, mice were immunized 11 times over 4-5 weeks using the Helios Gene Gun system according to the manufacturer’s instructions (BioRad). Briefly, expression vectors encoding wild type human FAP was coated onto gold beads (BioRad) and delivered to the epidermis of a shaved mouse abdomen. For soluble protein immunizations, mice were immunized with a human FAP recombinant protein representing the extracellular domain. Animals were immunized with recombinant protein mixed with Alum and CpG-ODN 10 times over 4-5 weeks using sub-cutaneous injections. The initial injection was 10 µg and subsequent boosts were 5 µg. FAP-specific serum titers were monitored by live-cell FACS analysis on an Accuri flow cytometer (BD Biosciences) using transiently transfected 293T cells. Animals with the highest antigen-specific serum titers against human FAP were sacrificed and used for hybridoma generation (Kohler and Milstein, 1975). Pooled lymphocytes from spleen and / or draining lymph node (from each harvest) were dissociated from lymphoid tissue by grinding in a suitable medium (for example, Dulbecco’s Modified Eagle Medium (DMEM); Invitrogen, Carlsbad, CA). B cells were selected and / or expanded using standard methods, and fused with a suitable fusion partner using techniques that were known in the art. Hybridoma supernatants with binding to human FAP and cynomolgus FAP were then selected for further characterization. Table 1 summarizes the number of antigen-specific hits identified. TABLE 1. Number of antigen specific antibodies against human and cynomolgus FAP protein identified from Xenomouse campaigns Harvest ImmunogenHuman FAP-specificCyno FAP-cross reactive bindersbinders 1 DNA 960 330 2. Additional binding characterization of anti-FAP antibodies

[0298] A subset of the exhausted hybridoma supernatants were tested for binding to human and cynomolgus FAP by flow cytometry. To confirm human and cynomolgus FAP binding and lack of human DPP4 binding, HEK293T cells were transiently transfected with a mammalian expression construct encoding human FAP, cynomolgus FAP, mouse FAP, or human DPP4 using 293Fectin (Thermo Fisher). To confirm binding of the antibodies to endogenously expressed human FAP, RPMI- 7951 cells endogenously expressing human FAP were also used to test the exhausted hybridoma supernatants. As a negative control, SKML-28 cells that lack endogenous FAP expression were used. Cells were incubated with exhausted hybridoma supernatants normalized to 5 ug / mL of antibody followed by Alexa Fluor 647 conjugated goat anti-human IgG secondary antibody (Jackson ImmunoResearch). Dead cells were stained with 7-Aminoactinomycin D (Sigma). Cells were run on Accuri flow cytometer to detect anti-FAP antibody binding. In general, there was a good correlation between human FAP and cynomolgus FAP binding and also between endogenous human FAP and transiently expressed human FAP binding. A single antibody was found to cross-react to mouse FAP while no cross-reactivity to human DPP4 was observed for any of the antibodies tested. Tables 2-4 summarize the binding characterization of these antibodies. TABLE 2. Binding characterization of anti-FAP antibodies Number of Human Cyno FAP Endogenous Mou Human Harvest samples FAP i i human FAP se FAP i DPP4 Table 3. Binding to 293T cells transiently expressing human FAP ^, cyno FAP ^, mouse FAP ^ and human DPP4 (FACS GeoMean values) ConcentrHuman Mouse Mock Human IDationFAP ^ Cyno FAP ^ FAP ^ DPP4 n 6E12 5 1277 236638 176669 38388 1202 6A1 5 1089 307257 169141 1259 1149 control Ab0 935 793 555 900 972 ID Concentration SKMEL28  RPMI‐7951  (ug / mL) GeoMean  GeoMean  0.08  803  5391  0.04  788  3243    3. Epitope bin

[0299] A common way to characterize epitopes is through competition experiments. Antibodies that compete with each other can be thought of as binding the same or overlapping site on the target. This example describes a method of determining competition for binding to human FAP and the results of the method when applied to a number of antibodies described herein.

[0300] Binning experiments can be conducted in a number of ways, and the method employed may have an effect on the assay results. Common to these methods is that FAP is typically bound by one reference antibody and probed by another. If the reference antibody prevents the binding of the probe antibody then the antibodies are said to be in the same bin. The order in which the antibodies are employed is important. If antibody A is employed as the reference antibody and blocks the binding of antibody B the converse is not always true: antibody B used as the reference antibody will not necessarily block antibody A. There are a number of factors in play here: the binding of an antibody can cause conformational changes in the target which prevent the binding of the second antibody, or epitopes which overlap but do not completely occlude each other may allow for the second antibody to still have enough high-affinity interactions with the target to allow binding. In general, if competition is observed in either order the antibodies are said to bin together, and if both antibodies can block each other then it is likely that the epitopes overlap more completely.

[0301] For this example, a modified antibody-antibody competition assay was used to determine the relative epitope binning profiles of the FAP specific antibodies in a high throughput manner. Briefly, individual antibodies were tested for their ability to compete for binding with a panel of reference antibodies chosen based on their different binding characteristics based on rough bins determined from preliminary data generated using a small set of samples representing different harvests. The pattern of competition / binding of each test antibody with the reference antibody panel was then determined and compared to those produced from the other test antibodies. The degree of correlation between the individual test antibody competition / binding profiles was then compared. Antibodies that showed similar competition / binding profiles were binned (grouped) together (eg. Binning Profile A, B, etc.).

[0302] Biotinylated recombinant soluble human FAP protein was coupled to streptavidin coated, uniquely barcoded LumAvidin Beads® (Luminex) for 45 minutes in the dark at room temperature and washed twice. The reference antibody hybridoma supernatant samples were incubated with the antigen-coated beads for 1 hour in the dark at room temperature and washed three times. Beads were resuspended in FACS buffer containing Stabilguard® (SurModics). The antigen-coated, reference antibody-bound beads were pooled and then divided into individual sample wells containing a normalized (5 ug / ml) test antibody (hybridoma supernatant) sample (or negative control), incubated for 1 hour in the dark at room temperature and washed twice. The samples were then incubated with Alexa Fluor® 488 IgG fragment-specific detection antibody (Jackson ImmunoResearch) for 15 minutes in the dark at room temperature, washed once and resuspended in FACS buffer. Samples were analyzed using an Accuri flow cytometer with Intellicyt HyperCyt autosampler.

[0303] To determine the antibody competition / binding profiles of the individual test antibodies, the reference-only antibody binding signal was subtracted from the reference plus test antibody signal for each competition / binding reaction (ie. across the entire reference antibody set). An individual antibody binding profile was defined as the collection of net binding values for each competition / binding reaction. The degree of similarity between individual profiles was then assessed by calculating the coefficient of determination between each of the test antibody profiles. Test antibodies showing high degrees of similarity (R2 > 0.8) to each other were then grouped into common binning profiles. Separate binning profiles were only defined if there were two or more samples with a high degree of correlation. If individual unique antibody binning profiles were observed (ie. they displayed a low degree of similarity to other test antibody binding profiles), the bin was classified as unknown. Of the 554 samples tested, 499 were sub-divided into 14 unique binning profiles. Table 5 summarizes the binning data showing number of samples in each bin for three harvests. TABLE 5. Antibody binning profile of anti-FAP antibodies Bin Harvest 1 Harvest 2 Harvest 3 Total A 2 142 120 264 4. Molecular Rescue and Sequencing of anti-FAP antibodies

[0304] RNA (total or mRNA) was purified from wells containing the anti-FAP antibody-producing hybridoma cells using a Qiagen RNeasy mini or the Invitrogen mRNA catcher plus kit. Purified RNA was used to amplify the antibody heavy and light chain variable region (V) genes using cDNA synthesis via reverse transcription, followed by a polymerase chain reaction (RT-PCR). The fully human antibody gamma heavy chain was obtained using the Qiagen One Step Reverse Transcriptase PCR kit (Qiagen). This method was used to generate the first strand cDNA from the RNA template and then to amplify the variable region of the gamma heavy chain using multiplex PCR. The 5’ gamma chain-specific primer annealed to the signal sequence of the antibody heavy chain, while the 3’ primer annealed to a region of the gamma constant domain. The fully human kappa light chain was obtained using the Qiagen One Step Reverse Transcriptase PCR kit (Qiagen). This method was used to generate the first strand cDNA from the RNA template and then to amplify the variable region of the kappa light chain using multiplex PCR. The 5’ kappa light chain-specific primer annealed to the signal sequence of the antibody light chain while the 3’ primer annealed to a region of the kappa constant domain. The fully human lambda light chain was obtained using the Qiagen One Step Reverse Transcriptase PCR kit (Qiagen). This method was used to generate the first strand cDNA from the RNA template and then to amplify the variable region of the lambda light chain using multiplex PCR. The 5’ lambda light chain-specific primer annealed to the signal sequence of light chain while the 3’ primer annealed to a region of the lambda constant domain.

[0305] The amplified cDNA was purified enzymatically using exonuclease I and alkaline phosphatase and the purified PCR product was sequenced directly. Amino acid sequences were deduced from the corresponding nucleic acid sequences bioinformatically. Two additional, independent RT-PCR amplification and sequencing cycles were completed for each hybridoma sample in order to confirm that any mutations observed were not a consequence of the PCR. The derived amino acid sequences were then analyzed to determine the germline sequence origin of the antibodies and to identify deviations from the germline sequence. A comparison of each of the heavy and light chain sequences to their original germline sequences are indicated. The amino acid sequences corresponding to complementary determining regions (CDRs) of the sequenced antibodies were aligned and these alignments were used to group the clones by similarity.

[0306] Using above described methodology, 82 unique heavy chains from 41 different VDJ recombination were resolved. Of these antibodies, light chain sequences for 2 antibodies from each VDJ group were resolved resulting in identification of 37 sequence-resolved unique antibodies identified from 29 different VDJ groups. Of these, 24 sequence-unique antibodies with 24 different CDR3s coming from 24 different VDJ groups were selected for bispecific molecule generation (Table 6). Bin C and Bin D are sub-bins and can be considered as substantially the same. TABLE 6. Anti-FAP antibodies ID Bin VH Germline VL Germline 6E5 A VH2|2-26 / D5|5-18|RF3 / JH6 VL1|1c / JL1 6E12 A VH3|3-21 / D5|5-18|RF3 / JH6 VL1|1c / JL2 EXAMPLE 2. Generation and characterization of FAP-targeting bispecific molecules

[0307] This example describes the generation and characterization of FAP-targeted bispecific molecules. The bispecific molecules are in IgG-scFv format, wherein an agonist for a T-cell co- stimulatory molecule is in IgG format, and the FAP binding moiety is an scFv that is attached to the C- terminus of the IgG. The molecule comprises copies of anti-FAP scFv, each attached to one C- terminus of one heavy chain of the IgG, making it a tetravalent bispecific molecule (Table 7).

[0308] A panel of FAP-targeting bispecific molecules were evaluated for binding to soluble forms of human and cynomolgus monkey FAP (Table 8) using the Octet assay. Association rate (Kon), disassociation rate (Kdis), and equilibrium binding constant (KD) were calculated. The majority of bispecific molecules showed high affinity binding to both human and cynomolgus monkey FAP. These bispecific molecules were next evaluated for their ability to induce FAP-dependent activation of human B cells. CHO cells expressing human FAP, CHO cells expressing cynomolgus monkey FAP, or CHO cells without FAP expression were seeded into a 96 well plate. The next day varying concentrations of the bispecific molecules were added to the wells along with purified human B cells or human PBMC and the plates were incubated for an additional 48 – 72 hours. Upregulation of CD86, a marker of B cell activation, was quantified on B cells by flow cytometry by using CD20 as B cell marker. EC50 values for CD86 upregulation by CD20+ cells were calculated and demonstrate that the majority of the bispecific molecules were able to induce B cell activation in the presence of CHO cells expressing human FAP or cynomolgus monkey FAP while all but one showed no agonist activity in the absence of FAP expression (Table 9). Table 7. FAP-targeting IgG-scFv bispecific molecules Antibody ID IgG scFv (FAP) 18799-1 Antibody A 35A10 18823-1 Antibody A 35F1 19017-1 Antibody A 6E1 Table 8 an and cynomolgus Human FAP Cyno FAP Antibody KD Kon Kdi (1 / )KD Kon Kdi (1 / s)5 5 5 - 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 5 5 5 5 Table 9. FAP-targeting bispecific molecule functional activity on human B cells in the presence of CHO cells expressing human or cynomolgus monkey FAP Control Human FAP.CHO Cyno FAP.CHO CHO EXAMPLE 3. Identification of epitope and paratope residues of FAP-binding proteins

[0309] This example describes structural studies that identified the epitope and paratope residues of FAP- binding proteins disclosed herein. 1. Materials and Methods

[0310] Purification of FAP in complex with scFv 32211. Molecule 32211 is a scFv fragment based on clone 6G12. The sequence of 32211 is shown as SEQ ID NO: 393. Human soluble FAP fragment is shown as residues 29-760 of SEQ ID NO: 394.

[0311] Human FAP was transiently expressed in Expi293FTMwith a 6xHistidine (SEQ ID NO: 397) tag at C-terminus and purified through the Ni-NTA column with imidazole gradient elution. The protein was further purified to homogeneity via size-exclusion chromatography using HiLoad 26 / 200 Superdex 200 (GE Healthcare). FAP with scFv 32211 complex was formed by mixing 1 mg FAP and 0.6 mg scFv 32211. The complex was obtained by removing excess scFv 32211 using size-exclusion chromatography followed by SDS-PAGE to confirm the presence of purified complex in the isolated peak. The purified FAP with scFv 32211 complex was concentrated to 12.6 mg / ml for crystallization setup.

[0312] Crystallization. Crystals of the FAP with scFv 32211 complex were obtained in the following condition: 0.2 M Sodium acetate, 20% PEG 3350, and the sitting drop vapor diffusion technique by mixing 100 nL protein with 100 nL crystallization buffer using the mosquito instrument (SPT Labtech). This condition yielded prism-like crystals that diffracted to 2.8 Å.

[0313] X-ray Crystallography data collection. Crystals were transiently cryo-protected using 85% crystallization buffer with 15% ethylene glycol. The SER-CAT staff performed the synchrotron data collection at the APS 22-ID beamline. Image frames were processed using HKL2000 software (HKL Research Inc.). The crystal belongs to space group P6122 with unit cell: a=123.37 Å, b=123.37 Å, c=336.022 Å; ^= ^=90º, ^=120º.

[0314] Structural determination and refinement. The structure was solved by molecular replacement using the published FAP structure (1Z68) and a homology model of the scFv 32211 as templates. The molecule replacement solution suggested that one FAP monomer and one scFv molecule were packed into the asymmetric unit with high confidence. After several rounds of iterative model building and structural refinement using Coot (Acta Cryst. D.) and Phenix (Acta Cryst. D66, 213-221, 2010), the final refinement Rwork / Rfree factors are 0.208 / 0.259. The structure is in good geometry with RMSD of bonds of 0.004 Å and RMSD angles of 0.7º; the Ramachandran plot shows 91.96% residues are in favorable backbone dihedral angles, and 7.5% residues are allowed. 2. Epitope and Paratope analysis

[0315] The overall crystal structure of human FAP in complex with the scFv 32211 is shown in FIG.1A.

[0316] In the crystal structure, the asymmetric unit contains one FAP monomer and one scFv 32211; the FAP dimerization interface and scFv 32211 / FAP interface are involved in the crystal contact formation. The FAP dimer with two scFv 32211 complex structure was obtained by crystallographic symmetry expansion. Therefore, the two interfaces between the FAP dimer and the two scFv 32211 are considered identical, and only one scFv / FAP interface is discussed. The overall crystal structure of FAP with scFv 32211 resembles a butterfly with two scFv 31122 molecules binding to surface loop regions of FAP at the tip of its fore wings (FIG.3A). The structure was visualized using Pymol (Schrodinger, LLC, New York, N.Y.).

[0317] Close examinations revealed that the scFv 32211 binds to three FAP surface loops, primarily through its VH domain (FIG.1B). These loops are composed of FAP residues 174-185, 267-278, and 326-327. The numbering is based on SEQ ID NO.394 for FAP and SEQ ID NO.393 for scFv 32211.

[0318] Table 10A shows the scFv 32211 residues which contact FAP. As shown in the table, Kabat CDR- H1 residues, N31, R33, and V34 contact FAP residues Y274, V275, G276, P277, Q278, D326, Y327; Kabat framework residues F27 and S28 contact FAP residues Y274 and D326; Kabat framework residue R99, and Kabat CDR-H3 I100, G101, G102, Y103, Y107, Y108, and D112 contact FAP residues F181, Q182, I183, F185, I267, P272, A273, Y274, G276, and P277; Kabat framework residues Y189, D200 and Kabat CDR-L2 S190, N192, Q193 and R194 contact FAP residues Q174, R175, D178, D178, P179, P180, F181, P272, and A273. While residues F27, S28 and S30 are considered “framework” residue immediately adjacent to CDR-H1 under Kabat definition, “Chothia” definition. “AbM” definition, and “IMGT” definition characterize these residues as part of CDR-H1. See Table 10F. Similarly, R99 and Y189 are considered framework residues under Kabat, but are part of CDR-H3 or CDR-L2 under alternative definitions. Table 10A. Summary of FAP epitope residues interacting with scFv 32211 paratope residues (residues within 4.5 Å of each other) FAP residues scFv 32211 residues (residue number based on SEQ ID NO: 394) (residue number based on SEQ ID NO: 393) GLN193 GLN182 TYR108 TYR103

[0319] We further characterized the importance of the epitope and paratope residues identified in Tables 10B and 10C. For example, when contacts are primarily with the backbone, or when the contacts are energetically neutral, the residue may tolerate a wide range of mutations. Significant contacts of an entire side chain with the other binding partner, or high conservation in a computational evolution simulation, are evidence that a particular residue may have increased importance relative to other residues. Table 10B. Ranking of the FAP residue importance in the binding interface FAP residues Importance Notes # er PHE181 Primary Favorable hydrophobic interaction with sidechain of Y108, Y103, S190, and Q193 GLN182 Primary Hydrogen bond of backbone carbonyl with sidechain of Y108 27 Table 10C. Ranking of the scFv 32211 residue importance in the binding interface scFv 32211 Position Importance Notes residues # according 7, SER28 H28 (FR) Optional Contacts with D326 ILE100 H95 Optional Contacts with Y274

[0320] Additionally, we analyzed whether certain epitope and paratope residues can tolerate or not tolerate certain mutations based on structural data, and these analyses are summarized as Tables 10D and 10E. Table 10D. Point mutations...

Claims

WHAT IS CLAIMED:

1. A Fibroblast-activation protein ^ (FAP) antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said protein comprises: (1) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 197, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 198; (2) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 199, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 200; (3) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 201, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 202; (4) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 203, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 204; (5) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 205, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 206; (6) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 207, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 208; (7) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 209, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 210; (8) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 211, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 212; (9) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 213, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 214; (10) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 215, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 216; (11) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 217, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 218; (12) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 219, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 220; (13) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 221, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 222; (14) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 223, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 224; (15) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 225, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 226; (16) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 227, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 228;(17) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 229, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 230; (18) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 231, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 232; (19) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 233, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 234; (20) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 235, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 236; (21) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 237, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 238; (22) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 239, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 240; (23) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 241, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 242; (24) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 243, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 244; (25) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 245, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 246; (26) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 247, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 248; (27) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 249, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 250; (28) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 251, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 252; (29) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 253, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 254; (30) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 255, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 256; (31) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 257, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 258; (32) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 259, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 260; (33) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 261, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 262; (34) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 263, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 264;(35) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 265, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 266; (36) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 267, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 268; (37) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 269, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 270; (38) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 271, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 272; (39) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 273, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 274; (40) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 275, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 276; (41) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 277, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 278; (42) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 279, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 280; (43) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 281, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 282; (44) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 283, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 284; (45) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 285, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 286; (46) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 287, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 288; (47) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 289, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 290; (48) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 291, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 292; (49) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 293, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 294; (50) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 295, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 296; (51) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 297, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 298; (52) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 299, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 300;(53) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 301, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 302; (54) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 303, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 304; (55) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 305, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 306; (56) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 307, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 308; (57) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 309, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 310; (58) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 311, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 312; (59) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 313, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 314; (60) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 315, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 316; (61) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 317, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 318; (62) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 319, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 320; (63) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 321, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 322; (64) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 323, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 324; (65) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 325, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 326; (66) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 327, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 328; (67) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 329, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 330; (68) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 331, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 332; (69) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 333, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 334; (70) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 335, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 336;(71) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 337, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 338; (72) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 339, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 340; or (73) the heavy chain CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 341, and the light chain CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO:

342.

2. The FAP antigen-binding protein of claim 1, comprising: (1) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.1-6, respectively; (2) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.6-12, respectively; (3) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.13-18, respectively; (4) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.19-24, respectively; (5) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.25-30, respectively; (6) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.31-36, respectively; (7) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.37-42, respectively; (8) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.43-48, respectively; (9) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.49-54, respectively; (10) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.55-60, respectively; (11) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.61-66, respectively; (12) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.67-72, respectively; (13) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.73-78, respectively; (14) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.79-84, respectively; (15) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.85-90, respectively;(16) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.91-96, respectively; (17) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.97-102, respectively; (18) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.103-108, respectively; (19) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.109-114, respectively; (20) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.115-120, respectively; (21) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID NOs.121-126, respectively (22) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.127-132, respectively; (23) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.133-138, respectively; (24) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.139-144, respectively; (25) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.145-150, respectively; (26) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.151-156, respectively; (27) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.157-162, respectively; (28) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.163-168, respectively; (29) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.169-174, respectively; (30) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.175-180, respectively; (31) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.181-186, respectively; (32) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.187-192, respectively; (33) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.43, 44, 45, 46, 47, and 193, respectively;(34) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.43, 44, 194, 46, 47, and 193, respectively; (35) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.175, 176, 177, 178, 179, and 195, respectively; (36) a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising SEQ ID Nos.187, 188, 196, 190, 191, and 192, respectively; (37) a CDR-H1 comprising any one of SEQ ID NOs: 398-402; a CDR-H2 comprising any one of SEQ ID NOs: 403-407; a CDR-H3 comprising any one of SEQ ID NOs: 408-412; a CDR-L1 comprising any one of SEQ ID NOs: 413-417; a CDR-L2 comprising any one of SEQ ID NOs: 418-422; and a CDR-L3 comprising any one of SEQ ID NOs: 423-427; (38) a CDR-H1 comprising any one of SEQ ID NOs: 428-432; a CDR-H2 comprising any one of SEQ ID NOs: 433-437; a CDR-H3 comprising any one of SEQ ID NOs: 438-442; a CDR-L1 comprising any one of SEQ ID NOs: 443-447; a CDR-L2 comprising any one of SEQ ID NOs: 448-452; and a CDR-L3 comprising any one of SEQ ID NOs: 453-457; (39) a CDR-H1 comprising any one of SEQ ID NOs: 458-462; a CDR-H2 comprising any one of SEQ ID NOs: 463-467; a CDR-H3 comprising any one of SEQ ID NOs: 468-472; a CDR-L1 comprising any one of SEQ ID NOs: 473-477; a CDR-L2 comprising any one of SEQ ID NOs: 478-482; and a CDR-L3 comprising any one of SEQ ID NOs: 483-487; or (40) a CDR-H1 comprising any one of SEQ ID NOs: 488-492; a CDR-H2 comprising any one of SEQ ID NOs: 493-497; a CDR-H3 comprising any one of SEQ ID NOs: 498-502; a CDR-L1 comprising any one of SEQ ID NOs: 503-507; a CDR-L2 comprising any one of SEQ ID NOs: 508-512; and a CDR-L3 comprising any one of SEQ ID NOs: 513-517.

3. A Fibroblast-activation protein ^ (FAP) antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said protein binds to an epitope that comprises residues V275, R175, F181, Q182, I183, D178, F185, P179, and Y274, according to the numbering of SEQ ID NO:

394.

4. The FAP antigen-binding protein of claim 3, wherein said VH and VL comprise (VH and VL numberings according to Kabat): (1) H33 is Arg, Lys, Gln, or Asn; (2) H94 is; Arg, Lys, Gln, or Asn; (3) H97 is Gly or Ala; (4) H98 is Tyr, Trp, Phe, Thr, or Ser; (5) H100B is Tyr, Trp, Phe, Thr, or Ser, (6) H100C is Tyr, Trp, Phe, Thr, or Ser; (7) L53 is Gln, Asn, or Glu; (8) L54 is Arg, Lys, Gln, or Asn; and (9) L60 is Asp, Glu, or Asn.

5. The FAP antigen-binding protein of claim 3 or 4, wherein: (a) said VH comprises: (i) a complementarity determining region (CDR)-H1 comprising any one of SEQ ID NOs: 398-402; and (ii) a CDR-H3 comprising any one of SEQ ID NOs: 408-412; (b) said VL comprises a CDR-L2 comprising any one of SEQ ID NOs: 418-422; and(c) said VL further comprises a D at position L60 (numbering according to Kabat).

6. A Fibroblast-activation protein ^ (FAP) antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said protein binds to an epitope that comprises E325, D331, Q336, I320, R324, E302, R303, and T335, according to the numbering of SEQ ID NO:

394.

7. The FAP antigen-binding protein of claim 6, wherein said VH comprises (VH numbering according to Kabat): (1) H31 is Arg, Lys, Gln, or Asn; (2) H98 is Tyr, Trp, Phe, Thr, or Ser; (3) H99 is Tyr, Trp, Phe, Thr, or Ser; (4) H100 is Tyr, Trp, Phe, Thr, or Ser; and (5) H101 is Asp, Glu, or Asn.

8. The FAP antigen-binding protein of claim 6 or 7, wherein: (a) said VH comprises: (i) a complementarity determining region (CDR)-H1 comprising any one of SEQ ID NOs: 428-432; and (ii) a CDR-H3 comprising any one of SEQ ID NOs: 438-442; and (b) said VL comprises a CDR-L2 comprising any one of SEQ ID NOs: 448-452.

9. A Fibroblast-activation protein ^ (FAP) antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said protein binds to an epitope that comprises S86, E82, I181, T83, Q85, Q65, K486, N80, T88, I485 and I487, according to the numbering of SEQ ID NO:

394.

10. The FAP antigen-binding protein of claim 9, wherein said VH comprises (VH numbering according to Kabat): (1) H31 is Asn, Gln, His, Asp, Lys, or Arg; (2) H33 is Gly, or Ala; (3) H52A is Tyr, Trp, Phe, Thr, or Ser; (4) H55 is Arg, Lys, Gln, or Asn; (5) H56 is Asn, Gln, His, Asp, Lys, or Arg; (6) H95 is Asp, Glu, or Asn; (7) H100 is Gly or Ala; (8) L32 is Tyr, Trp, Phe, Thr, or Ser; (9) L91 is Phe, Leu, Val, Ile, Ala, or Tyr; and (10) L95 is Tyr, Trp, Phe, Thr, or Ser.

11. The FAP antigen-binding protein of claim 9 or 10, wherein: (a) said VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 458-462; (ii) a CDR-H3 comprising any one of SEQ ID NOs: 463-467; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 468-472; and (b) said VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 473-487; (ii) a CDR-L2 comprising any one of SEQ ID NOs: 478-482; and (iii) a CDR-L3 comprising any one of SEQ ID NOs: 483-487.

12. A Fibroblast-activation protein ^ (FAP) antigen-binding protein comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein said protein binds to an epitope that comprises K381, K371, E414, S428, Q389, Y432, I390, P434, and K436, according to the numbering of SEQ ID NO:394.

13. The FAP antigen-binding protein of claim 12, wherein said VH and VL comprise (VH and VL numbering according to Kabat): (1) H28 is Thr or Ser; (2) H53 is Asp, Glu, or Asn; (3) H96 is Arg, Lys, Gln, or Asn; (4) H99 is Tyr, Trp, Phe, Thr, or Ser; (5) H100A is Tyr, Trp, Phe, Thr, or Ser; (6) H100B is Tyr, Trp, Phe, Thr, or Ser; and (7) H100C is Tyr, Trp, Phe, Thr, or Ser.

14. The FAP antigen-binding protein of claim 12 or 13, wherein: (a) said VH comprises: (i) a CDR-H1 comprising any one of SEQ ID NOs: 488-492; (ii) a CDR-H2 comprising any one of SEQ ID NOs: 493-497; and (iii) a CDR-H3 comprising any one of SEQ ID NOs: 498-502; and (b) said VL comprises: (i) a CDR-L1 comprising any one of SEQ ID NOs: 503-507; and (ii) a CDR-L3 comprising any one of SEQ ID NOs: 513-517.

15. The FAP antigen-binding protein of any one of claims 1-14, comprising: a VL framework derived from a human germline V ^ framework sequence or a human germline V ^ framework sequence, and a VH framework derived from a human germline VH1, VH2, VH3, VH4, or VH5 framework sequence.

16. The FAP antigen-binding protein of any one of claims 1-15, which is an IgG.

17. The FAP antigen-binding protein of any one of claims 1-15, which is an antigen-binding fragment of an IgG.

18. The FAP antigen-binding protein of any one of claims 1-15, which is a single chain Fv (scFv).

19. The FAP antigen-binding protein of 18 wherein said scFv comprises a first linker between VH and VL.

20. A nucleic acid comprising a nucleotide sequence encoding the FAP antigen-binding protein of any one of claims 1-19.

21. A host cell comprising the nucleic acid of claim 20.

22. A pharmaceutical composition comprising (i) the FAP antigen-binding protein of any one of claims 1-19; and (ii) a pharmaceutically acceptable carrier, excipient, or diluent.

23. A method of making the FAP antigen-binding protein of any one of claims 1-19, under a condition wherein the FAP antigen-binding protein is expressed.

24. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the FAP antigen-binding protein of any one of claims 1-19, or the pharmaceutical composition of claim 22.

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