Multivalent antibodies comprising Anti-PD-1 and Anti-CD2 antibody regions

Abstract

Provided herein, inter alia, are compositions including multivalent antibodies comprising anti-CD2 antibody regions and anti-PD-1 antibody regions. The multivalent antibodies are particularly effective for suppressing T cells and activating PD-1-associated immunosuppressive activity, and are further contemplated to be effective for treating autoimmune and inflammatory diseases.

Description

[0001] 062460-503001WG

[0002] Multivalent Antibodies Comprising Anti- PD-1 and An ti-CD2 Antibody Regions

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U. S. Provisional Patent Application No. 63 / 734,749 filed December 16, 2024, U. S. Provisional Patent Application No. 63 / 799,758, filed May 5, 2025, U. S. Provisional Patent Application No. 63 / 862.019, filed August 12. 2025, and U. S. Provisional Patent Application No. 63 / 878,122, filed September 9, 2025, each of which is incorporated by reference herein in its entirety.

[0004] INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0005] This application contains a Sequence Listing which has been submitted in. XML format via EFS-WEB and is hereby incorporated by reference in its entirety. Said. XML copy, created on December 16, 2025, is named 062460-503001WO.xml and is 964 kilobytes in size BACKGROUND PD-1 is an essential inhibitory co-receptor expressed on chronically activated CD4 and CD8 T cells. In autoimmune patients, pathogenic T cells often express high levels of PD-1; however, their proinfl ammatory and tissue-damaging effector functions suggest PD-1 engagement by its ligands PD-L1 and PD-L2 is limiting, and that supplementation with PD-1 -agonizing therapies should inhibit disease progression. Proposed mechanisms behind suboptimal PD-1 ligand exposure in autoimmunity include low PD-L1 or PD-L2 expression, PD-L1 or PD-L2 shedding, and sequestration of PD-L1 by high levels of CD80, a CD28 co-stimulatory ligand that also inhibits PD-L1 binding to PD-1. Importantly, the development of organ-specific autoimmune disease in cancer patients treated with PD-1 inhibiting antibodies (e.g. colitis, arthritis, thyroiditis, and type 1 diabetes) highlights the key role PD-1 plays in restraining autoreactive T cells.

[0006] Several PD-1 -agonist monoclonal antibodies (mAbs) are currently in preclinical or clinical development. Most PD-1 agonist mAbs are IgGl antibodies that function by / rom-ligation of PD-1 to Fc-receptors (FcRs) on antigen presenting cells (APCs), resulting in PD-1 recruitment to the immune synapse and TCR inhibition; however, other outcomes may include deletion of protective PD-U T cells — such as CD4+follicular helper T (Tfh) cells and CD8+tissue resident T (Trm) cells — by ADCC / ADCP and undesired promfl ammatory signaling from crosslinked Fc receptors FcyRIIA or FcyRIIIA. Furthermore, FcyRIIA or FcyRIIIA polymorphisms that reduce IgGl Fc binding affinities may also limit the numbers of responding patients, as these polymorphisms are known to attenuate functionality of therapeutic IgGl. 062460-503001WG SUMMARY

[0007] An aspect of the present disclosure is a multivalent antibody comprising at least one anti-PD-1 antibody region and at least one anti-CD2 antibody region.

[0008] In embodiments, the multivalent antibody recognizes and binds to a PD-1 antigen and to a CD2 antigen on an effector cell, e.g., a T cell.

[0009] In embodiments, the binding of the multivalent antibody to CD2 antigens on the effector cell promotes PD-1 activation.

[0010] In embodiments, the multivalent antibody does not disrupt binding to the CD2 ligand CD58.

[0011] In embodiments, the multivalent antibody promotes recruitment of PD-1 / CD2 complexes to the immunological synapse by CD58 expressed on antigen presenting cells.

[0012] In embodiments, the binding of the multivalent antibody to CD2 antigens on the effector cell recruits PD-1 to the synapse by bridging it in cis to the costimulatory receptor CD2.

[0013] In embodiments, the multivalent antibody stimulates PD-1 phosphorylation and association with the T cell-inhibiting phosphatase SHP2.

[0014] In embodiments, binding of the multivalent antibody to antigens on the effector cell modulates the signaling pathways downstream of CD2.

[0015] In embodiments, the multivalent antibody inhibits effector cell proliferation.

[0016] In embodiments, binding of the multivalent antibody to antigens on the effector cell decreases IL-2 production and / or IFN-y production by the effector cell.

[0017] In embodiments, the multivalent antibody does not induce pro-inflammatory pathways via FcR engagement.

[0018] In embodiments, the multivalent antibody suppresses IFNy expression from antigen stimulated PBMCs irrespective of FcR genotype.

[0019] In embodiments, the multivalent antibody inhibits the effector cell and / or activates immunomodulatory signals to the effector cell.

[0020] In embodiments, the multivalent antibody reduces the effector cell’s cytotoxic response towards an autologous cell.

[0021] In embodiments, the multivalent antibody provides greater inhibition effector cell activity, promotion of immunomodulatory signals, and / or reduced effector cell proliferation relative to a monospecific anti -PD-1 antibody.

[0022] In embodiments, the multivalent antibody provides greater PD-1 receptor occupancy and / or PD-1 blockade than the monospecific anti-PD-1 antibody.

[0023] In embodiments, the multivalent antibody suppresses and prevents disease progression in graft-versus-host disease (GVHD). 062460-503001WG In embodiments, the multivalent antibody comprises an antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a sequence shown in one or more of Table 1 to Table 11.

[0024] In embodiments, the multivalent antibody comprises at least two VHHs.

[0025] In embodiments, one VHH comprises an anti-PD-1 antibody region and one VHH comprises an anti-CD2 antibody region.

[0026] In embodiments, the multivalent antibody comprises at least three VHHs.

[0027] In embodiments, a first VHH comprises an anti-PD-1 antibody region, a second VHH comprises an anti-CD2 antibody region, and a third VHH comprises an anti-HS A antibody region.

[0028] In embodiments, the VHH comprising the anti-PD-1 antibody region is N-terminal to one or both of the VHH comprising the anti-CD2 antibody region and / or the VHH comprising the anti-HS A antibody region.; the VHH comprising the anti-CD2 antibody region is N-terminal to one or both of the VHH comprising the anti- PD-1 antibody region and / or the VHH comprising the anti-HSA antibody region; or the VHH comprising the anti-HSA antibody region is N-terminal to one or both of the VHH comprising the anti- PD-1 antibody region and / or the VHH comprising the anti-CD2 antibody region. In embodiments, the multivalent antibody comprises one of the following configurations (progressing N-terminal to C-terminal): PD1: CD2: HSA; PD1: HSA: CD2; CD2: PD1: HSA; HSA: PD1: CD2; HSA: CD2: PD1; or CD2: HSA: PD1.

[0029] In embodiments, the VHH comprising the anti-HSA antibody region detuned in that it comprises one or more mutations relative to a wild type anti-HSA VHH (e g., SEQ ID NO: 940) such that it has reduced affinity to HSA.

[0030] In embodiments, the VHH comprising the anti-HSA antibody region detuned in that it comprises two or more mutations, three or more mutations, four or more mutations, or five or more mutations relative to a wild type anti-HSA VHH (e.g., SEQ ID NO: 940) such that it has reduced affinity to HSA.

[0031] In embodiments, the VHH comprising the anti-HSA antibody region comprises a sequence at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 941 to 988, e.g., 958, 977. and 983.

[0032] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, and an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2. and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively.

[0033] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 062460-503001WG 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780, and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 781 or 782.

[0034] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751 and an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604.

[0035] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780, and a constant region that is at least 90% identical (e.g.. 95%. 99%. or 100% identical) to one of SEQ ID NO: 781 or 782.

[0036] In embodiments, the scVhh-74 multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1. CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HS A antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 998 (GFTFSSFG), SEQ ID NO: 999 (ISGSGSDT), and SEQ ID NO: 1000 (TIGGGLSR) respectively.

[0037] In embodiments, the scVhh-94 multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3 comprising SEQ ID NO: 1001 (GFTFRSFG), SEQ ID NO: 1002 (ISGSGSDT), and SEQ ID NO: 1003 (TISGSLSR) respectively.

[0038] In embodiments, the scVhh-100 multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 062460-503001WG 1004 (GFTFRSFG), SEQ ID NO: 1005 (ISGSGSDT), and SEQ ID NO: 1006 (TIGGVLSR) respectively.

[0039] In embodiments, the scVhh-74 multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1. CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HS A antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 1007 (GFTFSSFG), SEQ ID NO: 1008 (ISGSGSDT), and SEQ ID NO: 1009 (GGGLSR) respectively.

[0040] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 958, 977, or 983.

[0041] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g.. 95%. 99%. or 100% identical) to SEQ ID NO: 781, and an anti HSA antibody region that is at least 90% identical (e g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 958, 977, or 983.

[0042] In embodiments, the anti-PD-1 antibody region is N-terminal to one or both of the anti-CD2 antibody region and / or the anti-HSA antibody region; the anti-CD2 antibody region is N-terminal to one or both of the anti- PD-1 antibody region and / or the anti-HSA antibody region; or the anti-HSA antibody region is N-terminal to one or both of the anti- PD-1 antibody region and / or the anti-CD2 antibody region. In some cases, the multivalent antibody has a configuration, progressing N-terminal to C-terminal, of PD1: CD2: HSA; PD1: HSA: CD2; CD2: PD1: HSA; HSA: PD1: CD2; HSA: CD2: PD1; or CD2: HSA: PD1.

[0043] In embodiments, the multivalent antibody includes a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 897.

[0044] In embodiments, the multivalent antibody includes a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 924.

[0045] In embodiments, the multivalent antibody includes a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 930. 062460-503001WG Any of the herein disclosed multivalent antibodies may further comprise a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780 and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 781 or 782.

[0046] Another aspect is a method of treating, preventing, or reducing the severity of an autoimmune disease or inflammatory disease, the method comprising contacting an effector cell with an effective amount of any herein disclosed multivalent antibody.

[0047] An additional other aspect is a method of treating, preventing, or reducing the severity of an autoimmune disease or inflammatory disease in a subject in need thereof, the method comprising contacting an effector cell with an effective amount of any herein disclosed multivalent antibody.

[0048] A further aspect is a method of treating, preventing, or reducing the severity of an autoimmune disease or inflammatory disease in a subject, the method comprising administering to the subject an effective amount of any herein disclosed multivalent antibody.

[0049] In embodiments, the autoimmune diseases or inflammatory disease is Type 1 diabetes (T1D), Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Myasthenia gravis (MG), Autoimmune uveitis (AU), Sjogren's syndrome (SjS), Inflammatory bowel diseases (IBD), or Autoimmune hepatitis (AIH), Behcet's disease (BD).

[0050] In an aspect, the present disclosure provides a method of treating, preventing, or reducing the severity of a graft-versus-host disease (GVHD), the method comprising contacting an effector cell with an effective amount of any herein disclosed multivalent antibody.

[0051] In an aspect, the present disclosure provides a method of treating, preventing, or reducing the severity of a graft-versus-host disease (GVHD) in a subject in need thereof, the method comprising contacting an effector cell with an effective amount of the multivalent antibody of any herein disclosed multivalent antibody.

[0052] In another aspect, the present disclosure provides a method of treating, preventing, or reducing the severity of a graft-versus-host disease (GVHD) in a subject, the method comprising administering to the subject an effective amount of the multivalent antibody of any herein disclosed multivalent antibody.

[0053] In embodiments, the method further comprise administering to the subject an effective amount of an immunomodulatory drug, e.g., a checkpoint inhibitor, adoptive T cell therapy, monoclonal antibody therapy, corticosteroid, tumor necrosis factor inhibitor, interleukin- 1 (IL-1) inhibitor, interleukin-6 (IL-6) inhibitor, T cell inhibitor, B-cell inhibitor, or Janus Kinase inhibitor. In some cases, the immunomodulatory drug is an immunosuppressant. In various embodiments, the method further comprises administering an effective amount of a standard of care therapy. 062460-503001WQ In a further aspect, the present disclosure provides pharmaceutical composition comprising any herein disclosed multivalent antibody and a pharmaceutically acceptable carrier, diluent, or excipient.

[0054] In embodiments, the pharmaceutical composition is for use as a medicament in the treatment of an autoimmune disease or inflammatory disease or in the treatment of a graft-versus-host disease (GVHD).

[0055] In an additional aspect, the present disclosure provides pharmaceutical composition comprising any herein disclosed multivalent antibody and an effective amount of an anti-PD-1 antibody, e.g., rosnilimab and peresolimab, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0056] In an yet another aspect, the present disclosure provides polynucleotide or plurality of polynucleotides encoding a herein disclosed multivalent antibody. In embodiment, the present disclosure provides a vector comprising the polynucleotide or plurality of polynucleotides.

[0057] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0058] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A is a schematic showing the role a PD1 x CD2 multivalent antibody plays in the recruitment of PD-1 / CD2 complexes to the immunological synapse by CD58 expressed on antigen presenting cells. PD1 x CD2 multivalent antibodies (mvAbs) stimulate PD-1 phosphory lation and association wi th the T cell-inhibiting phosphatase SHP2.

[0059] FIG. 1B-1H displays illustrative, non-limiting, multivalent antibody formats. In FIG. 1H shows four illustrative linkers comprising the sequences of SEQ ID NO: 936 to 939. An antibody format may have two identical linkers or two different linkers. Also shown in a C-terminal domains which may be a poly A (i.e., AAA) or a His-TEV-Fc which comprises the sequences of, at least SEQ ID NO: 989. Any Fc domain recited herein can be included in a His-TEV-Fc.

[0060] FIG. 2A is a graph showing IL-2 production by Jurkat-PDlhlghand Jurkat-PDlmidcells co-cultured with wild ty pe Raji cells, Raji cells engineered to express! G4-aLY TCR specific for an NY-ESO-1 peptide (pNY: SLLMWITQV) presented by HLA-A2 or Raji cells engineered to express 1G4-aLY TCR and PDL-1.

[0061] FIG. 2B is a graph showing CD69 expression by Jurkat-PDlhlghand Jurkat-PDlmidcells cocultured with wild type Raji cells, Raji cells engineered to express! G4-aLY TCR specific for an NY-ESO-1 peptide (pNY: SLLMWITQV) presented by HLA-A2 or Raji cells engineered to express! G4-aLY TCR and PDL-1. 062460-503001WG FIG. 3A is a graph showing IL-2 production by Jurkat-PDlmidcells cocultured with Raji-A2 cells and treated with PDIVhhD x CD2FabA.

[0062] FIG. 3B is a graph showing IL-2 production by Jurkat-PDlhlghcells cocultured wi th Raji-A2 cells and treated with PDIVhhD x CD2FabA.

[0063] FIG. 4A is a graph showing IL-2 production by Jurkat-PDlmidcells cocultured with Raji-A2 cells and treated with PD1 VhhA x CD2FabL.

[0064] FIG. 4B is a graph showing IL-2 production by Jurkat-PDlmidcells cocultured with Raji-A2 cells and treated with PDIVhhA x CD2FabL with blockade of CD28 ligands with CTLA-4. Ig (bottom) or without blockade (top).

[0065] FIG. 5 is a graph showing IL-2 production by Jurkat-PDlmidcells cocultured with Raji-A2 and treated with a PDIVhhA x CD2FabN mvAb or a mixture of PDIVhhA x Fc and Fc x CD2FabN single-arm Abs.

[0066] FIG. 6 is a set of graphs showing binding characteristics of the CD2 VHHs identified in the CD2 VHH screen. The binding affinities of the CD2 domains for human and cynomolgus monkey CD2 were determined by Octet RH16 using SA biosensors (Sartorius). The purified test articles were screened for functionality with the Jurkat-PDlmid+ Raji-A2 assay in a 384-well format.

[0067] FIG. 7 is a graph showing IL-2 production by Jurkat-PDlmidcells cocultured with Raji-A2 cells and treated with a subset of CD2 x PD1 mvAbs and “2+1"’ mvAbs as indicated.

[0068] FIG. 8A is a graph showing CD69 expression in Jurkat-PD1-Y248F compared to PD1-WT cells treated with PDIVhhA x CD2FabL or a CD2 x Fc monovalent control.

[0069] FIG. SB is a graph showing CD69 expression in Jurkat-PDl- Y223F, Y248F compared to PD1-WT cells treated with PDIVhhA x CD2FabL or a CD2 x Fc monovalent control.

[0070] FIG. 9A is quantification of the SHP2 / PD1 ratio in Jurkat-PDl Raji-A2 co-cultures treated with PDIVhhA x CD2FabL or Fc x CD2FabL or a CD2 x Fc monovalent control.

[0071] FIG. 9B is quantification of the SHP2 / PD1 ratio in Jurkat-PDl Raji-A2 co-cultures and Jurkat-PDl cells alone treated with PDIVhhA x CD2FabM mvAb or the PDIVhhA x Fc mono-specific Ab.

[0072] FIG. 10 is a graph showing IFN-y production from a mixed lymphocyte reaction (MLR) assay. PDIVhhJ x CD2VhhB and Fc x CD2VhhB monospecific Ab were added to the MLR to test their ability to suppress IFN-y production.

[0073] FIG. 11A is a graph showing IFN-y production from PBMC (200,000) from a CMV+donor stimulated for 4 days with CMV antigens and treated with 2 different PD1 x CD2 mvAbs (PDIVhhJ x CD2VhhB and PDIVhhJ x CD2VhhAL). Respective Fc x CD2 mono-specific Abs w ere also tested in this experiment. 062460-503001WG FIG. 1 IB is a graph quantifying IFN-y production from PBMC (200,000) from a CMV+donor stimulated for 4 days with CMV antigens and treated with two different PD-1 agonist IgGl mAbs were also tested (rosnilimab and peresolimab; which are identified in the figure, respectively, as PDlIgGl A and PDlIgGIB).

[0074] FIG. 12A is a graph quantifying CD4+ T cell proliferation in a tonsil T cell + moDC MLR in the presence of PDIVhhA x CD2FabL, Fc x CD2FabL, PDIVhhA x Fc, or rosnilimab (identified in the figure as PDlIgGl A).

[0075] FIG. 12B is a graph quantifying TNF production by T cells in a tonsil T cell + moDC MLR in the presence of PDIVhhA x CD2FabL, Fc x CD2FabL, PDIVhhA x Fc, or rosnilimab (identified in the figure as PDlIgGl A).

[0076] FIG. 13 is a graph quantifying IFN-y production from a T cell recall response. PBMC were cultured for 5 days with a mixture of CEFX peptides (JPT) and tetanus toxid (TT), resulting in PD-1 expression on CEFX and TT-specific T cells. PBMCs were then restimulated with autologous moDC + CEFX / TT with PDIVhhA x CD2FabL or Fc x CD2FabL, for three days. FIG. 14A is a graph quantifying IL-2 production from Jurkat-PD-1 cell co-cultured with Raji-A2 cells and treated with PDIVhhJ x CD2VhhAP, PDIVhhJ x CD2VhhF, PDIVhhJ x CD2VhhAB or anti-CD2 clone 9.6.

[0077] FIG. 14B is a graph quantifying IL-2 production from Jurkat-PD-1 CD58 knockout cells cocultured with Raji-A2 cells and treated with PDIVhhJ x CD2VhhAP, PDIVhhJ x CD2VhhF, PDIVhhJ x CD2VhhAB or anti-CD2 clone 9.6.

[0078] FIG. 14C is a graph quantifying IL-2 production from Jurkat-PD-1 cell co-cultured with Raji-A2 CD58 knockout cells and treated with PDIVhhJ x CD2VhhAP, PDIVhhJ x CD2VhhF, PDIVhhJ x CD2VhhAB or anti-CD2 clone 9.6.

[0079] FIG. 15A is a graph showing changes in body weight for mice treated with multivalent antibodies of the present disclosure.

[0080] FIG. 15B (left and right) are graphs showing PD-1 receptor occupancy in cells contacted with multivalent antibodies of the present disclosure.

[0081] FIG. 16 are graphs showing PD reduced CD71 and ICOS expression by cells contacted with multivalent antibodies of the present disclosure.

[0082] FIG. 17 is a graph showing the effects of FcyRIIIA polymorphisms on antibody-dependent cellular cytotoxicity (ADCC) when cells are contacted with an anti-PD-1 agonist antibody rosnilimab (identified in the figure as PDlIgGl A).

[0083] FIG. 18A is a graph showing PD-1 expression on activated T cells, and FIG. 18B is a graph showing ADCC of activated primary PD-1+ CD4 T cells in the presence of PBMC of different FcyRIIIa genotypes and rosnilimab (identified in the figure as PDlIgGlA). 062460-503001WG FIG. 19 is a graph showing the effects of PD-1 -mediated FcR crosslinking by PD-1 agonist IgGl mAbs.

[0084] FIG. 20 includes graphs of FcyRIIIa-genotyped NK cell-mediated killing activity of various antibody formats: rosnilimab (top left, identified as PDlIgGlA), peresolimab (top right, identified as PDlIgGIB), and an illustrative antibody of the present disclosure (bottom. PDIVhhA x CD2FabL).

[0085] FIG. 21 includes graphs showing potent PD-1 agonism by multivalent antibodies of the present disclosure in the Jurkat-PDl assay.

[0086] FIG. 22A and FIG. 22B includes graphs showing T cell suppression by scVHH and Fc-fused mvAbs by MLR with either human serum supplementation (FIG. 22A) or bovine serum supplementation (FIG. 22B).

[0087] FIG. 23 includes a graph showing data from scVHH constructs having the HSA- or the PD1-specific VHH replaced with a VHH specific for Campylobacter jejuni flagella (CjeF), which has no binding activity in the experimental system.

[0088] FIG. 24 includes graphs showing receptor occupancy (RO) in cells that express PD-1 (left graphs) or that lack PD-1 expression (right graphs).

[0089] FIG. 25 includes graphs comparing an scVHH of the present disclosure with the benchmark PD-1 agonist antibody in inhibition of inflammatory cytokines or chemokines.

[0090] FIG. 26A to FIG. 26D are graphs showing the effect of PD-1 tyrosine mutations on scVHHs or PD1 x CD2 KiH mvAbs of the present disclosure.

[0091] FIG. 27 is a graph showing that anti-HSA VHH variants, which comprise one or more mutations relative to a wild type anti-HSA VHH (“detuned anti-HSA VHHs”), and have lower affinities for HSA that correlate with those predicted by MOE software.

[0092] FIG. 28A and FIG. 28B are graphs showing the potency of “HSA-detuned” scVHHs in a Jurkat / Raji assay in the presence of human serum.

[0093] FIG. 29A and FIG.29B are graphs showing that the “HSA-detuned” scVHH formats enable high potency in primary cell assays in the presence of human serum.

[0094] FIG. 30A and FIG. 30B are graphs showing PD1 x CD2 multivalent antibodies suppress a Type 1 diabetes patient’s T cell response to pancreatic islet antigens.

[0095] FIG. 31A is a graph showing decreased expression of the cytokine IL-21 and FIG. 12B is a graph showing decreased expression of the chemokine CXCL13 in PBMCs obtained from a Rheumatoid arthritis (RA) patient when treated with PDlxCD2 bispecific antibodies of the present disclosure, compared to control.

[0096] FIG.32A and FIG.32B are graphs showing the activity of two PD1. CD2. HSA scVHH test articles and a benchmark PD-1 mAb in an FcyRIIIa-genotj ped PBMC CEFX response assay. 062460-503001WG FIG. 33 is a graph showing the stimulation of PD-1 / SHP2 association by the indicated PD1 x CD2 test articles in a Jurkat / Raji assay containing human serum.

[0097] FIG. 34A and FIG. 34B are graphs showing affinities of PD1. CD2. HSA scVHH test articles for HSA and their potency in a Jurkat / Raji assay containing human serum, and the correlation between the two values.

[0098] FIG. 34C is a graph showing the activity of the indicated PD1. CD2. HSA scVHH test articles in a T cell + moDC MLR.

[0099] FIG. 35A and FIG. 35B are graphs show ing the pharmacokinetics of scVHH test articles in mice expressing human serum albumin.

[0100] DETAILED DESCRIPTION

[0101] The present invention relates to multivalent antibodies comprising at least one anti-PD-1 antibody region and at least one anti-CD2 antibody region.

[0102] The inventors have discovered that that PD-1 signaling can be stimulated in an FcR-independent manner with multivalent antibodies (e.g., bispecific antibodies or bsAbs) that link PD-1 to the T cell co-stimulatory receptor CD2 on the surface of the same cell, e.g., T cell. Employing anti-CD2 antibody domains that do not disrupt binding to the CD2 ligand CD58, the PD1 x CD2 mvAbs described herein enable recruitment of PD-1 / CD2 complexes to the immunological synapse by CD58 expressed on antigen presenting cells (FIG. 1A to FIG. 1H) PD1 x CD2 mvAbs stimulate PD-1 phosphorylation and association with the T cell-inhibiting phosphatase SHP2. In primary immune cell assays, the PD1 x CD2 mvAbs suppress T cell proliferation and production of cytokines. In irradiated immunodeficient mice reconstituted w ith human PBMC, the PD1 x CD2 mvAbs suppress graft-versus-host disease (GVHD). As CD58 is expressed on both immune APCs and non-immune cells, a therapeutic based on the PD1 x CD2 mvAbs described herein should resolve pathology driven by autoantigens presented on both immune and non-immune cells in diverse autoimmune or inflammatory conditions.

[0103] Programmed Death-1 (PD-1) refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 and PD-L2. The term " PD-T?as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. PD-1 is a cell surface receptor that can be expressed on T cells and B cells and can play a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity’. This prevents autoimmune disease or inflammatory diseases, but it can also prevent the immune system from killing cancer cells which express or overexpress PD-L1 or PD- 062460-503001WG L2. PD-1 is an immune checkpoint and guards against autoimmunity through two mechanisms. First, it inhibits T cell responses (e.g. cytotoxicity and IFN-y production) and / or promotes apoptosis (programmed cell death) in antigen-specific T-cells. Second, it reduces apoptosis in regulator}' T cells (anti-inflammatory, suppressive T cells).

[0104] CD2 is a cell adhesion molecule found on the surface of T cells and natural killer (NK) cells. It has also been called T-cell surface antigen T1 l / Leu-5, LFA-2, LFA-3 receptor, erythrocyte receptor and rosette receptor. CD2 can interact with other adhesion molecules, such as lymphocyte function-associated antigen-3 (LFA-3 / CD58) in humans, or CD48 in rodents, which are expressed on the surfaces of other cells. In addition to its adhesive properties, CD2 also acts as a costimulatory molecule on T and NK cells. CD2 can have an important role in the formation and organization of the immunological synapse that is formed between T cells and antigen-presenting cells upon cell-cell conjugation and associated intracellular signaling. CD2 expression can be upregulated on memory' T cells as well as activated T cells and plays an important role in activation of memory T cells. Anti-CD2 monoclonal antibodies have been shown to induce immune modulatory effects in vitro and clinical studies have proven the safety and efficacy of CD2-targeting biologies.

[0105] Multivalent Antibodies

[0106] Provided herein are multivalent antibodies including: (i) an anti -PD-1 antibody region capable of recognizing and binding a PD-1 epitope, e.g., of a PD-1 protein expressed by an effector cell including a T cell; and (ii) a CD2 antibody region capable of recognizing and binding a CD2 epitope, e.g., of a CD2 protein expressed by the effector cell.

[0107] As used herein, the term multivalent antibody is any polypeptide chain, fusion protein, protein, protein complex, and the like that can recognize and bind both a PD-1 epitope and a CD2 epitope. In some cases, the term ‘’PD1 x CD2’’ is here used to represent every' envisioned multivalent antibody of the present disclosure. Illustrative multivalent antibodies are shown in FIG. IB, FIG. ID, FIG. 1G, and FIG. 1H. Some illustrative antibodies comprise Fc regions having either a knob or a hole; see, e.g., FIGs. 1B-F1G. 1G; here, the knob is shown as the circular protrusion and the hole as the indentation. In other cases, multivalent antibodies comprise Fc regions lacking a knob and a hole. Shown in FIG. 1H are illustrative serially linked single variable domains on a heavy chain (VHH); as shown, the serially linked VHH comprise a plurality of VHH domain directed to a plurality of different antigens. In embodiments, the serially linked VHH lacks a constant domain, e.g., an Fc domain. In other embodiments, the serial linked VHH comprises a constant domain. FIG. 1H shows that a serial linked VHH has an AAA or a constant region (exemplified there as His-TEV-Fc); how ever, a serial linked VHH can have both an AAA and a 062460-503001WG constant region. Another term for a serially linked VHH is a single chain VHH or scVHH. FIG.

[0108] 1H also shows illustrative scVHH which include an Fc domain, which are embodiments having a C-terminal “His-TEV-Fc”.

[0109] The term “multivalent antibody” “multivalent antibodies” or “multivalent” or “multivalents” or “mvAb” or “mvAbs” as provided herein is used according to its conventional meaning well known in the art and refers to a multivalent recombinant protein capable of simultaneously binding to at least two different antigens, e.g., two different antigens (a “bispecific antibody”), three different antigens (a “trispecific antibody”) or four or more different antigens. In contrast to traditional monoclonal antibodies, multivalent antibodies, here bispecific antibodies, include two independently different antibody regions (i.e., an anti-PD-1 antibody region and an anti-CD2 antibody region). Binding of the multivalent antibody to an effector cell (e.g. T cell) may activate the effector cell or downregulate or inhibit immunomodulatory signals to the effector cell. In embodiments, binding of the multivalent antibody to the effector cell activates the effector cell. In embodiments, binding of the multivalent antibody to the effector cell modulates the effector cell. In some embodiments, the multivalent antibody which is a trispecific comprises three independently different antibody regions (i.e., an anti-PD-1 antibody region, an anti-CD2 antibody region, and an anti-HSA antibody region).

[0110] An “antibody region” as provided herein refers to a monovalent or multivalent protein moiety that forms part of the multivalent antibody provided herein including embodiments thereof and that can recognize and bind an antigen (epitope). The antibody region provided herein may include a domain of an antibody or fragment (e.g., Fab, single-chain variable fragment (scFv), and single variable domain on a heavy chain (VHH)) thereof. An antibody region comprises a sufficient number of, e.g., three, complementarity determining regions (CDRs) that permit recognition and binding of the PD-1 epitope or the CD2 epitope. An antibody region may include a light chain variable domain (VL) and / or a heavy chain variable domain (VH). In embodiments, the antibody region includes a light chain variable (VL) domain. In embodiments, the antibody region includes a heavy chain variable (VH) domain. In embodiments, the antibody region is an HH, also referred to as a nanobody. In embodiments, the antibody region is a Fab, Fab’, or scFv. In embodiments, the antibody region is an Fab. The multivalent antibody may include two Fabs, each of which binds a different antigen. In embodiments, the antibody region is a Fab’. In embodiments, the antibody region is an scFv. The multivalent antibody may include two scFvs, each of which binds a different antigen. In embodiments, the multivalent antibody comprises one or more VHH, one or more scFv, and / or one or more Fab; any combination of VHH, scFv, and VHH is envisioned. In embodiments, the antibody region is a peptibody. A “peptibody” as provided herein refers to a peptide moiety attached (through a covalent or non-covalent linker) to 062460-503001WG the Fc domain or fragment thereof of an antibody. In short, a multivalent antibody can be any polypeptide chain, fusion protein, protein, protein complex, and the like that comprises a sufficient number of, e.g., three, PD-1 -epitope-specific complementarity determining regions (CDRs) that permit recognition and binding of the PD-1 epitope and comprise a sufficient number of, e.g., three, CD2-epitope-specific CDRs that permit recognition and binding of the CD2 epitope.

[0111] Illustrative multivalent antibodies are shown in FIG. IB, FIG. ID, FIG. 1G, and FIG. 1H.

[0112] The multivalent of FIG. IB, comprises an anti-CD2 Fab and an anti-PD-1 VHH; the Fc domains show n here comprise a knob and a hole, Fc domains lacking the knob and hole are envisioned. Alternately, a multivalent of this general format has an anti-PD-1 Fab and an anti-CD2 VHH. The multivalent of FIG. ID, comprises an anti-PD-1 VHH and an anti-CD2 VHH; the Fc domains shown here comprise a knob and a hole, Fc domains lacking the knob and hole are envisioned. The multivalent of FIG. 1G, comprises two anti-PD-1 VHHs and an anti-CD2 VHH; the Fc domains shown here comprise a knob and a hole, Fc domains lacking the knob and hole are envisioned. Other multivalent antibodies that comprise one or more scFv, one or more Fab, and / or one or more VHH is considered. Multivalents can have two anti-PD-1 scFv and an anti-CD2 Fab; two anti-PD-1 scFv, one anti-PD-1 Fab, and one anti-CD2 Fab; two anti-CD2 scFv, one anti-PD-1 Fab, and one anti-CD2 Fab; one anti-PD-1 scFv, one anti-CD2 scFv, one anti-PD-1 Fab, and one anti-CD2 Fab; and other possible configurations. The multivalent of FIG. 1H, comprises one anti-CD2 VHH. one anti-PD-1 VHH and one anti-human serum albumin (HSA) VHH. Alternately, multivalents of this general format has the one anti-CD2 VHH, one anti-PD-1 VHH and one antihuman serum albumin (HSA) VHH in any order. The order of VHH is unlimited. In some cases a serially linked VHH comprises one VHH directed to CD2 and one to PD1; a serially linked VHH comprises more than one VHH directed to CD2 and one to PD1; a serially linked VHH comprises one VHH directed to CD2 and more than one VHH to PD1; a serially linked VHH comprises more than one VHH directed to CD2 and more than one VHH to PD1; and / or a serially linked VHH comprises one or more VHH directed to an antigen that promotes stability' and / or longevity' of a serially linked VHH. In embodiments, the serially linked VHH lacks a constant domain, e.g., an Fc domain. In other embodiments, the serial linked VHH comprises a constant domain. Another term for a serially linked VHH is a single chain VHH or scVHH.

[0113] Other antibody formats are considered. The monospecific antibody of FIG. 1C, comprises an anti-CD2 Fab; the Fc domains shown here comprise a knob and a hole, Fc domains lacking the knob and hole are envisioned. Alternately, an antibody of this general format comprises an anit-PD1 Fab. The monospecific antibody of FIG. IE, comprises an anti-PD-1 VHH; the Fc domains shown here comprise a knob and a hole, Fc domains lacking the knob and hole are envisioned. 062460-503001WG The monospecific antibody of FIG. IF, comprises an anti-CD2 VHH; the Fc domains shown here comprise a knob and a hole, Fc domains lacking the knob and hole are envisioned.

[0114] In some embodiments a VHH is attached to the Fc domain. In some embodiments, an scFv is attached to the hinge region of the antibody. In some embodiments a scFv is attached to the Fc domain. Any possible configuration of VHH, Fab, scFv, knob and hole or absence thereof, and attachment of VHH, Fab, and scFv to the multivalent is envisioned in the present disclosure.

[0115] An aspect of the present disclosure is a multivalent antibody comprising at least one anti-PD-1 antibody region and at least one anti-CD2 antibody region.

[0116] In embodiments, the multivalent antibody recognizes and binds to a PD-1 antigen and to a CD2 antigen on an effector cell, e.g.. a T cell.

[0117] In embodiments, the binding of the multivalent antibody to CD2 antigens on the effector cell promotes PD-1 activation.

[0118] In embodiments, the multivalent antibody does not disrupt binding to the CD2 ligand CD58.

[0119] In embodiments, the multivalent antibody promotes recruitment of PD-1 / CD2 complexes to the immunological synapse by CD58 expressed on antigen presenting cells.

[0120] In embodiments, the binding of the multivalent antibody to CD2 antigens on the effector cell recruits PD-1 to the synapse by bridging it in cis to the costimulatory receptor CD2.

[0121] In embodiments, the multivalent antibody stimulates PD-1 phosphorylation and association with the T cell-inhibiting phosphatase SHP2.

[0122] In embodiments, binding of the multivalent antibody to antigens on the effector cell modulates the signaling pathways downstream of CD2.

[0123] In embodiments, the multivalent antibody inhibits effector cell proliferation.

[0124] In embodiments, binding of the multivalent antibody to antigens on the effector cell decreases IL-2 production and / or IFN-y production by the effector cell.

[0125] In embodiments, the multivalent antibody does not induce pro-inflammatory pathways via FcR engagement.

[0126] In embodiments, the multivalent antibody suppresses IFN-y expression from antigen stimulated PBMCs irrespective of FcR genotype.

[0127] In embodiments, the multivalent antibody inhibits the effector cell and / or activates immunomodulatory signals to the effector cell.

[0128] In embodiments, the multivalent antibody reduces the effector cell’s cytotoxic response towards an autologous cell. 062460-503001WG In embodiments, the multivalent antibody provides greater inhibition effector cell activity, promotion of immunomodulatory signals, and / or reduced effector cell proliferation relative to a monospecific anti -PD-1 antibody.

[0129] In embodiments, the multivalent antibody provides greater PD-1 receptor occupancy and / or PD-1 blockade than the monospecific anti-PD-1 antibody.

[0130] In embodiments, the multivalent antibody suppresses and prevents disease progression in graft-versus-host disease (GVHD).

[0131] As CD58 is expressed on both immune APCs and non-immune cells, a therapeutic based on the PD1 x CD2 mvAbs described herein should resolve pathology driven by autoantigens presented on both immune and non-immune cells in diverse autoimmune or inflammatory conditions.

[0132] In embodiments, the effector cell is a CD8+ T cell (e.g., a CD8+ CD4- T cell), a CD4+ T cell (e.g., a CD8- CD4+ T cell), a gamma delta (yS) T cell, an invariant T cell, a natural killer (NK) cell, an invariant natural killer cell (iNK cell), an invariant natural killer T cell (iNKT cell), or a macrophage.

[0133] In embodiments, the effector cell is a T cell.

[0134] In embodiments, the T cell is a CD4+ T cell or a CD8+ T cell.

[0135] In embodiments, the multivalent antibody includes an antibody region including a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a sequence shown in one or more of Table 1 to Table 11.

[0136] In embodiments, the multivalent antibody includes an antibody region including a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a sequence shown in one or more of Table 1 to Table 3 and a sequence that is at least 90% identical (e.g.. 95%. 99%. or 100% identical) to a sequence shown in one or more of Table 4 to Table 7.

[0137] In embodiments, the multivalent antibody includes a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a sequence shown in Table 9.

[0138] In embodiments, an anti-CD2 antibody region is configured as a Fab, a single-chain variable fragment (scFv), and / or a single variable domain on a heavy chain (VHH).

[0139] In embodiments, an anti-CD2 antibody region is configured as a Fab, a single-chain variable fragment (scFv), and / or a single variable domain on a heavy chain (VHH).

[0140] In embodiments, the multivalent antibody includes at least tw o anti-CD2 antibody regions. In embodiments, the multivalent antibody includes at least three anti-CD2 antibody¬ regions.

[0141] In embodiments, an anti-PD-1 antibody region is configured as a Fab, a single-chain variable fragment (scFv), and / or a single variable domain on a heavy chain (VHH). 062460-503001WG In embodiments, the multivalent antibody includes at least two anti-PD-1 antibody regions. In embodiments, the multivalent antibody includes at least three anti-PD-1 antibody regions.

[0142] In embodiments, the multivalent antibody includes one or more Fabs, includes one or more scFvs, and / or includes one or more VHHs.

[0143] In embodiments, the multivalent antibody includes at least two Fabs.

[0144] In embodiments, a first Fab includes an anti-PD-1 antibody region and a second Fab includes an anti-CD2 antibody region.

[0145] In embodiments, the multivalent antibody includes at least one Fab and at least one VHH. In embodiments, the at least one Fab includes an anti-PD-1 antibody region and the at least one VHH includes an anti-CD2 antibody region.

[0146] In embodiments, the at least one Fab includes an anti-CD2 antibody region and the at least one VHH includes an anti-PDl antibody region.

[0147] In embodiments, the multivalent antibody includes at least one Fab and at least one scFv. In embodiments, the at least one Fab includes an anti-PD-1 antibody region and the at least one scFv includes an anti-CD2 antibody region.

[0148] In embodiments, the at least one Fab includes an anti-CD2 antibody region and the at least one scFv includes an anti-PDl antibody region.

[0149] In embodiments, the multivalent antibody includes at least two Fabs and includes at least one VHH.

[0150] In embodiments, both Fabs include an anti-PD-1 antibody region.

[0151] In embodiments, both Fabs include an anti-CD2 antibody region.

[0152] In embodiments, a first Fab includes an anti-PD-1 antibody region and a second Fab includes an anti-CD2 antibody region.

[0153] In embodiments, the at least one VHH includes an anti-PD-1 antibody region.

[0154] In embodiments, the at least one VHH includes an anti-CD2 antibody region.

[0155] In embodiments, the multivalent antibody includes at least two Fabs and includes at least one scFv.

[0156] In embodiments, both Fabs include an anti-PD-1 antibody region.

[0157] In embodiments, both Fabs include an anti-CD2 antibody region.

[0158] In embodiments, a first Fab includes an anti-PD-1 antibody region and a second Fab includes an anti-CD2 antibody region.

[0159] In embodiments, the at least one scFv includes an anti-PD-1 antibody region.

[0160] In embodiments, the at least one scFv includes an anti-CD2 antibody region. In embodiments, the multivalent antibody includes at least two Fabs and includes at least two VHHs.

[0161] In embodiments, both Fabs include an anti-PD-1 antibody region.

[0162] In embodiments, both Fabs include an anti-CD2 antibody region.

[0163] In embodiments, a first Fab includes an anti-PD-1 antibody region and a second Fab includes an anti-CD2 antibody region.

[0164] In embodiments, both VHHs include an anti-PD-1 antibody region.

[0165] In embodiments, both VHHs include an anti-CD2 antibody region.

[0166] In embodiments, one VHH includes an anti-PD-1 antibody region and one VHH includes an anti-CD2 antibody region.

[0167] In embodiments, one VHH includes an anti-PD-1 antibody region, one VHH includes an anti-CD2 antibody region, and one VHH includes an anti-HSA antibody region. In some cases, the multivalent antibody is a serially linked VHH. In embodiments, the serially linked VHH lacks a constant domain, e.g., an Fc domain. In other embodiments, the serial linked VHH comprises a constant domain. See, FIG. 1H. FIG. 1H shows that a serial linked VHH has an AAA or a constant region (exemplified there as His-TEV-Fc); however, a serial linked VHH can have both an AAA and a constant region.

[0168] In embodiments, the multivalent antibody includes at least two Fabs and includes at least two scFvs.

[0169] In embodiments, both Fabs include an anti-PD-1 antibody region.

[0170] In embodiments, both Fabs include an anti-CD2 antibody region.

[0171] In embodiments, a first Fab includes an anti-PD-1 antibody region and a second Fab includes an anti-CD2 antibody region.

[0172] In embodiments, both scFvs include an anti-PD-1 antibody region.

[0173] In embodiments, both scFvs include an anti-CD2 antibody region.

[0174] In embodiments, one scFv includes an anti-PD-1 antibody region and one scFv includes an anti-CD2 antibody region.

[0175] In embodiments, the multivalent antibody comprises at least two VHHs.

[0176] In embodiments, one VHH comprises an anti-PD-1 antibody region and one VHH comprises an anti-CD2 antibody region.

[0177] In embodiments, the multivalent antibody comprises at least three VHHs.

[0178] In embodiments, a first VHH comprises an anti-PD-1 antibody region, a second VHH comprises an anti-CD2 antibody region, and a third VHH comprises an anti-HSA antibody region.

[0179] In embodiments, the VHH comprising the anti-PD-1 antibody region is N-terminal to one or both of the VHH comprising the anti-CD2 antibody region and / or the VHH comprising the anti- 062460-503001WG HSA antibody region.; the VHH comprising the anti-CD2 antibody region is N-terminal to one or both of the VHH comprising the anti- PD-1 antibody region and / or the VHH comprising the anti-HSA antibody region; or the VHH comprising the anti-HSA antibody region is N-terminal to one or both of the VHH comprising the anti- PD-1 antibody region and / or the VHH comprising the anti-CD2 antibody region. In embodiments, the multivalent antibody comprises one of the following configurations (progressing N-terminal to C-terminal): PD1: CD2: HSA; PD1: HSA: CD2; CD2: PD1: HSA; HSA: PD1: CD2; HSA: CD2: PD1; or CD2: HSA: PD1.

[0180] In embodiments, the VHH comprising the anti-HSA antibody region detuned in that it comprises one or more mutations relative to a wild type anti-HSA VHH (e g., SEQ ID NO: 940) such that it has reduced affinity to HSA.

[0181] In embodiments, the VHH comprising the anti-HSA antibody region detuned in that it comprises two or more mutations, three or more mutations, four or more mutations, or five or more mutations relative to a wild ty pe anti-HSA VHH (e.g., SEQ ID NO: 940) such that it has reduced affinity to HSA.

[0182] In embodiments, the VHH comprising the anti-HSA antibody region comprises a sequence at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 941 to 988, e.g., 958, 977, and 983.

[0183] Illustrative Antibody Regions, Antibodies, and Multivalent Antibodies

[0184] CD2

[0185] In embodiments, the multivalent antibody includes an antibody region including one to six complementarity determining regions (" CDRs") sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the CDR sequence shown in Table 1.

[0186] In embodiments, the multivalent antibody includes an antibody region including three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) sequences from a single row of Table 1, e.g., SEQ ID NO: 1 to SEQ ID NO: 3.

[0187] In embodiments, the multivalent antibody includes an antibody region including three Light Chain CDRs (CDR-L1, CDR-L2, and CDR-L3) sequences from a single row of Table 1, e.g., SEQ ID NO: 4 to SEQ ID NO: 6.

[0188] In embodiments, the multivalent antibody includes an antibody region including CDR-Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences from single a row of Table 1. e.g., SEQ ID NO: 1 to SEQ ID NO: 6.

[0189] In embodiments, a multivalent antibody comprising a sequence that is less than 100% identical to a sequence show n in Table 1 comprises one, two or three amino acid mutations which are independently a substitution mutation, a deletion mutation, an insertion mutation, or a Q SEID 062460-503001WG ( NOsLeft g) to riht combination thereof. CDRs recited throughout the present application are defined based on the Kabat numbering scheme. CDRs from the VH, VL and scFvs of the present application could also be defined by using other conventional antibody numbering schemes, i.e. IMGT or Chothia.

[0190] Table 1 CDRs Corresponding to CD2 antigen binding domains

[0191] Name CDR-H1 CDR-H2 CDR-H3 CDR-L1 CDR-L2 CDR-L3

[0192] l7l)AKYI)(i¥A" 'TSSKTTZHS^ i-6 CD2FabA SYWMH YNEKFKD LDY GNTYLY RMSNLAS MQHLEYPYT RIDPYDSETH RDAKYDGYA RSSKTLLHSN 7-12 CD2FabB SYWMH YNESFQG LDY GNTYLY RMSNLAS MQHLEYPYT RIDPYDSETH RDAKYDGYA RSSKTLLHSN 13-18 CD2FabC SYWMH YNPSFQG LDY GNTYLY RMSNLAS MQHLEYPYT RIDPYDSETH RDAKYDGYA RSSKTLLHSN 19-24 CD2FabD SYWMH YNPSFQG LDY GNTYLY RMSNLAS MQHLEYPYT RIDPYDSETH RDAKYDGYA RSSKTLLHSN 25-30 CD2FabE SYWMH YNPSFQG LDY GNTYLY RMSNLAS MQHLEYPYT RIDPYDSETH RDAKYDGYA RSSKTLLHSN 31-36 CD2FabF SYWMH YNPSFQG LDY GNTYLY RMSNLAS MQHLEYPYT RIDPYDSETH RDAKYDGYA RSSKTLLHSN 37-42 CD2FabG SYWMH YNPSFQG LDY GNTYLY RMSNLAS MQHLEYPYT RIDPYDSETH RDAKYDGYA RSSKTLLHSN RMSNLAS MQHLEYPYT 43-48 CD2FabH SYWMH YNPSFQG LDY GNTYLY

[0193] RIDPYDSETH RDAKYDGYA RSSKTLLHSN 49-54 CD2FabI SYWMH YNPSFQG LDY GNTYLY RMSNLAS MQHLEYPYT RIDPYDSETH RDAKYDGYA RSSKTLLHSN 55-60 CD2FabJ SYWMH YNPSFQG LDY GNTYLY RMSNLAS MQHLEYPYT RIDPYDSETH RDAKYDGYA RSSKTLLHSN 61-66 CD2FabK SYWMH YNPSFQG LDY GNTYLY RMSNLAS MQHLEYPYT RIDPEDGSIDY GKFNYRFAY RSSQSLLHSS LVSKLES MQFTHYPYT 67-72 CD2FabL F. YYMY VF. KFKK GNTYLN

[0194] RIDPEDGSIDY GKFNYRFAY RSSQSLLHSS LVSKLES MQFTHYPYT 73-78 CD2FabM EYYMY VEKFKK GNTYLN

[0195] CD2FabN SYWVN RIDPYDSETH SPRDSSTNLA RASQSISDYL YASQSIS QNGHSFPLT 79-84

[0196] YNQKFTD D H AISYIGSRTYY DTVFSTVLTP 85-87 CD2VhhA SLIMA EESVKG VAEKFDL

[0197] AISYIGSRTYY ETVFSTVLTP 88-90 CD2VhhB SLIMA EESVKG VAEKFDL

[0198] AISYIGSRTYY DTVFSTVLTP 91-93 CD2VhhC SLIMA EESVKG VAEKFDL

[0199] AISYIGSRTYY ETVFSTVLTP 94-96 CD2VhhD SLIMA EESVKG VAEKFDL

[0200] AISYIGSRTYY DTVFSTVMTP 97-99 CD2VhhE SLIMA EESVKG VYEKFDL

[0201] AISYIGSRTYY ETVFSTVMTP 100- CD2VhhF SLIMA EESVKG VYEKFDL 102

[0202] AISYIGSRTYY DTVFSTVLTP 103- CD2VhhG GLIMA EESVKG VAEKFDL 105

[0203] AISYIGSRTYY ETVFSTVLTP 106- CD2VhhH GLIMA EESVKG VAEKFDL 108

[0204] AISTGGGDTY APWLHLTSY 109- CD2VhhI TYAVG YLDSVKG WGTWAEYDT 111

[0205] AISTGGGDTY APWLHLTSYY 112- CD2VlihJ TYAVG YLDSVKG GTWAEYDT 114

[0206] AISYLGSRTY DTVFSTVMTP 115- CD2VhhK NLIMA YEESVKG VYEKFDL 117

[0207] AISYLGSRTY ETVFSTVMTP 118-

[0208]

[0209] CD2VhhL NLIMA YEESVKG VYEKFDL 120 AISYLGSRTY ETVFSTVLTP 121- CD2VhhM NLIMA YEESVKG VYEKFDL 123

[0210] AISYLGSRTY ETVFSTVMTP 124- CD2VhhN NLIMA YEESVKG VYEKFDL 126

[0211] AISYLGSRTY ETVFSTVLTP 127- CD2VhhO NLIMA YEESVKG VYEKFDL 129

[0212] AISTGGGDTY APWLHLTSY 150- CD2VhhP LYAVG YLDSVKG WGTWAEYDT 132

[0213] AISYIGSRTYY DTVFSTVLTP 133- CD2VhhQ GLIMA EESVKG VAEKFDL 135

[0214] AISYIGSRTYY ETVFSTVLTP 136- CD2VhhR GLIMA EESVKG VAEKFDL 138

[0215] AISYIGSRTYY ETVFSTVLTP 139- CD2VhhS GLIMA EESVKG VAEKFDL 141

[0216] AISYIGSRTYY DTVFSTVVTP 142- CD2VhhT SLIMA EESVKG AYEKFDL 144

[0217] AISYIGSRTYY ETVFSTVVTP 145- CD2VhhU SLIMA EESVKG AYEKFDL 147

[0218] AISYIGSRTYY ETVFSTVVTP 148- CD2VhhV SLIMA EESVKG AYEKFDL 150

[0219] AISTGGGSTY APWLHLTSY 151- CD2VhhW TYAVG YLDSVKG WGTWSEYDT 153

[0220] AISTGGGSTY APWLHLTSYY 154- CD2VhhX TYAVG YLDSVKG GTWSEYDT 156

[0221] AISYIGSRTYY DTVFSTILTPV 157- CD2VhhY SLIMA EESVKG YDKFDL 159

[0222] AISYIGSRTYY ETVFSTILTPV 160- CD2VhhZ SLIMA EESVKG YDKFDL 162

[0223] AISYDGSRTY DTVFSAVMTP 163- CD2VhhAA GLIMA YEESVKG VAEQFDL 165

[0224] AISYDGSRTY ETVFSAVMTP 166- CD2VhhAB GLIMA YEESVKG VAEQFDL 168

[0225] AISYDGSRTY DTVFAAVMT 169- CD2VhhAC NLIMA YEESVKG PVAEQFDL 171

[0226] AISYDGSRTY ETVFAAVMTP 172- CD2VhhAD NLIMA YEESVKG VAEQFDL 174

[0227] AISTGGGDTY APWLRLTSY 175- CD2VhhAE TYAVG YLDSVKG WGTWSEYDT 177

[0228] AISTGGGDTY APWLRLTSYY 178- CD2VhhAF TYAVG YLDSVKG GTWSEYDT 180

[0229] AISYLGSRTY DTVFSTVLTP 181- CD2VhhAG NLIMA YEESVKG VAEKFDL 183

[0230] AISYLGSRTY ETVFSTVLTP 184- CD2VhhAH NLIMA YEESVKG VAEKFDL 186

[0231] AISYLGSRTY ETVFSTVLTP 187- CD2VhhAI NLIMA YEESVKG VAEKFDL 189

[0232] AISYIGSRTYY DTVFAAVMT 190- CD2VhhAJ SLIMA EESVKG PVAEQFDL 192

[0233] AISYIGSRTYY ETVFAAVMTP 193- CD2VhhAK SLIMA EESVKG VAEQFDL 195

[0234] AISYIGSRTYY ETVFAAVLTP 196- CD2VhhAL SLIMA EESVKG VAEQFDL 198

[0235] AISYIGSRTYY ETVFAAVMTP 199- CD2VhhAM SLIMA EESVKG VAEQFDL 201

[0236] AISYIGSRTYY ETVFAAVLTP 202- CD2VhhAN SLIMA EESVKG VAEQFDL 204

[0237] AISYDGSRTY DTVFSTVLTP 205- CD2VhhAO SLIMA YEESVKG VYEKFDL 207

[0238] AISYDGSRTY ETVFSTVLTP 208- CD2VhhAP SLIMA YEESVKG VYEKFDL 210

[0239] AISYIGSRTYY DTVFSTVMTP 211- CD2VhhAQ SLIMA EESVKG KYEKFDL 213

[0240] AISYIGSRTYY ETVFSTVMTP 214- CD2VhhAR SLIMA EESVKG KYEKFDL 216

[0241] AISYIGSRTYY DTVFSTVLTP 217- CD2VhhAS SLIMA EESVKG VAEKFDL 219

[0242] AISYIGSRTYY DTVFSTVLTP 220-

[0243]

[0244] CD2VhhAT SLIMA EESVKG VAEKFDL 222 AISYIGSRTYY DTVFSTVMTP 223- CD2VhhAU SLIMA EESVKG VYEKFDL 225

[0245] AISYIGSRTYY DTVFSTVLTP 226- CD2VhhAV GLIMA EESVKG VAEKFDL 228 CD2VhhA AISTGGGDTY APWLHLTSY 229- W TYAVG YLDSVKG WGTWAEYDT 231

[0246] AISYLGSRTY DTVFSTVMTP 232- CD2VhhAX NLIMA YEESVKG VYEKFDL 234

[0247] AISTGGGDTY APWLHLTSY 235- CD2VhhAY LYAVG YLDSVKG WGTWAEYDT 237

[0248] AISYIGSRTYY DTVFSTVLTP 238- CD2VhhAZ GLIMA EESVKG VAEKFDL 240

[0249] AISYIGSRTYY DTVFSTVVTP 241- CD2VhhBA SLIMA EESVKG AYEKFDL 243

[0250] AISTGGGSTY APWLHLTSY 244- CD2VhhBB TYAVG YLDSVKG WGTWSEYDT 246

[0251] AISYIGSRTYY DTVFSTILTPV 247- CD EESVKG YDKFDL 249 2VhhBC SLIMA

[0252] AISYDGSRTY DTVFSAVMTP 250- CD2VhhBD GLIMA YEESVKG VAEQFDL 252

[0253] AISYDGSRTY DTVFAAVMT 253- CD2VhhBE NLIMA YEESVKG PVAEQFDL 255

[0254] AISTGGGDTY APWLRLTSY 256- CD2VhhBF TYAVG YLDSVKG WGTWSEYDT 258

[0255] AISYLGSRTY DTVFSTVLTP 259- CD2VhhBG NLIMA YEESVKG VAEKFDL 261

[0256] AISYIGSRTYY DTVFAAVMT 262- CD2VhhBH SLIMA EESVKG PVAEQFDL 264

[0257] AISYDGSRTY DTVFSTVLTP 265- CD2VhhBI SLIMA YEESVKG VYEKFDL 267

[0258] AISYIGSRTYY DTVFSTVMTP 268- CD2VhhBJ SLIMA EESVKG KYEKFDL 270

[0259] SAGNWNDHTI NAVASATTPQ 271- CD2VhhBK TYAMG YADSVKD YNY 273

[0260] DLSWRFDDIG DKNFDLPSTW 274- CD2VhhBL INTMG YADSVKG QSIDY 276

[0261] AISYIGSRTYY DTVFSTVLTP 277- CD2VhhBM SLIMA EESVKG VAEKFDL 279

[0262] AISYIGSRTYY DTVFSTVLTP 280- CD2VhhBN SLIMA EESVKG VAEKFDL 282

[0263] AISCIGSRTYY DTRVRIYAYT 283- CD2VhhBO NLIMA EESVKG DPTWYDY 285

[0264] AISYIGSRTYY DTVFSTVMTP 286- CD2VhhBP SLIMA EESVKG VYEKFDL 288

[0265] AISYIGSRTYY DTVFSTVLTP 289- CD2VhhBQ SLIMA EESVKG VAEKFDL 291

[0266] AISTGGGDTY DKNFDLPSTW 292- CD2VhhBR TYAVG YLDSVKG QSIDY 294

[0267] DLSWRFDDIG DKNFLPSTWQ 295- CD2VhhBS INTMG YADSVKG SIDY 297

[0268] DLSWRFDDIG APWLHLTSY 298- CD2VhhBT INTMG YADSVKG WGTWSEYST 300

[0269] AISYIGSRTYY DTVFSTVLTP 301- CD2VhhBU SLIMA EESVKG VAEKFDL 303

[0270] AISYIGSRTYY DTVFSTVLTP 304- CD2VhhBV SLIMA EESVKG VAEKFDL 306

[0271] DLSWRFDDIG DKNFDLPSTW 307- CD2VhhBW FNVMG YADSVKG QSIDY 309

[0272] DLSWRFDDIG DTVFSTVLTP 310- CD2VhhBX INTMG YADSVKG VAEKFDL 312

[0273] DLSWRFDDIG DKNFDLPSTW 313- CD2VhhBY INTMG YADSVKG QSIDY 315

[0274] DLSWRFDDIG DKNFDLPSTW 316- CD2VhhBZ INTMG YADSVKG QSIDY 318

[0275] DLSWRFDDIG VITAGSFTVR 319- YADSVKG CPLGVPHLYD 321

[0276]

[0277] CD2VhhCA INTMG Y DLSWRFDDIG DKNFDLPSTW 322- CD2VhhCB INTMG YADSVKG QSIDY 324

[0278] AISYDGSRTY DTVFSTVVTP 325- CD2VhhCC SLIMA YEESVKG AYEKFDL 327

[0279] AISYIGSRTYY DTVFSTVLTP 328- CD2VhhCD SLIMA EESVKG VAEKFDL 330

[0280] AISYIGSRTYY DTVFSTVLTP 331- CD2VhhCE SLIMA EESVKG VAEKFDL 333

[0281] AISYIGSRTYY DTVFSTVLTP 334- CD2VhhCF GLIMA EESVKG VAEKFDL 336

[0282] AISYIGSRTYY DTVFSTVLTP 337- CD2VhhCG SLIMA EESVKG VAEKFDL 339

[0283] AISYLGSRTY DTVFSTVMTP 340- CD2VhhCH NLIMA YEESVKG VYEKFDL 342

[0284] AISYSGSRTY ETVFSTVLTP 343- CD2VhhCI SLIMA YEESVKG VYEKFDL 345

[0285] AISYSGSRTY ETVFSTVLTP 346- CD2VhhCJ SLIMA YEESVKG VYEKFDL 348

[0286] AISYSGSRTY EAVFSTVLTP 349- CD2VhhCK SLIMA YEESVKG VYEKFDL 351

[0287] AISYSGSRTY ETAFSTVLTP 352- CD2VhhCL SLIMA YEESVKG VYEKFDL 354

[0288] AISYSGSRTY ETVASTVLTP 355- CD2VhhCM SLIMA YEESVKG VYEKFDL 357

[0289] AISYSGSRTY ETVFSTVLAP 358- CD2VhhCN SLIMA YEESVKG VYEKFDL 360

[0290] AISYSGSRTY ETVFSTVLTA 361- CD2VhhCO SLIMA YEESVKG VYEKFDL 363

[0291] AISYSGSRTY ETVFSTVLTP 364- CD2VhhCP SLIMA YEESVKG VYEYFDL 366

[0292] AISGSGSRTY ETVFSTVLTP 367- CD2VhhCQ SLIMA YEESVKG VYEKFDL 369

[0293] AISYSGGRTY ETVFSTVLTP 370- CD2VhhCR SLIMA YEESVKG VYEKFDL 372

[0294] AISYSGSSTYY ETVFSTVLTP 373- CD2VhhCS SLIMA EESVKG VYEKFDL 375

[0295] AISYSGSRTY ETVFSTVLTP 376- CD2VhhCT SLIMA YAESVKG VYEKFDL 378

[0296] AISYSGSRTY ETVFSTVLTP 379- CD2VhhCU SYIMA YEESVKG VYEKFDL 381

[0297] AISYSGSRTY ETVFSTVLTP 382- CD2VhhCV SLAMA YEESVKG VYEKFDL 384

[0298] AISYSGSRTY ETVFSTVLTP 385- CD2VhhCW ILIMA YEESVKG VYEKFDL 387

[0299] AISYSGSRTY ETVFSTVLTP 388- CD2VhhCX SSIMA YEESVKG VYEKFDL 390

[0300] AISSSGSRTYY ETVFSTVLTP 391- CD2VhhCY SLIMA EESVKG VYEKFDL 393

[0301] AISYSGSRTY EEVFSTVLTP 394- CD2VhhCZ SLIMA YEESVKG VYEKFDL 396

[0302] AISYSGSRTY ETLFSTVLTPV 397- CD2VhhDA SLIMA YEESVKG YEKFDL 399

[0303] AISYSGSRTY ETVGSTVLTP 400- CD2VhhDB SLIMA YEESVKG VYEKFDL 402

[0304] AISYSGSRTY ETVFSTVLTG 403- CD2VhhDC SLIMA YEESVKG VYEKFDL 405

[0305] AISYEGSRTY ETVFSTVLTP 406- CD2VhhDD SLIMA YEESVKG VYEKFDL 408

[0306] AISYEGSRTY ETVFSTVLTP 409- CD2VhhDE SLIMA YEESVKG VYEKFDL 411

[0307] AISYEGSRTY EAVFSTVLTP 412- CD2VhhDF SLIMA YEESVKG VYEKFDL 414

[0308] AISYEGSRTY ETAFSTVLTP 415- CD2VhhDG SLIMA YEESVKG VYEKFDL 417

[0309] AISYEGSRTY ETVASTVLTP 418- CD2VhhDH SLIMA YEESVKG VYEKFDL 420

[0310] AISYEGSRTY ETVFSTVLAP 421-

[0311]

[0312] CD2VhhDI SLIMA YEESVKG VYEKFDL 423 062460-503001WG AISYEGSRTY ETVFSTVLTA 424- CD2VhhDJ SLIMA YEESVKG VYEKFDL 426

[0313] AISYEGSRTY ETVFSTVLTP 427- CD2VhhDK SLIMA YEESVKG VYEYFDL 429

[0314] AISGEGSRTY ETVFSTVLTP 430- CD2VhhDL SLIMA YEESVKG VYEKFDL 432

[0315] AISYEGGRTY ETVFSTVLTP 433- CD2VhhDM SLIMA YEESVKG VYEKFDL 435

[0316] AISYEGSSTY ETVFSTVLTP 436- CD2VhhDN SLIMA YEESVKG VYEKFDL 438

[0317] AISYEGSRTY ETVFSTVLTP 439- CD2VhhDO SLIMA YAESVKG VYEKFDL 441

[0318] AISYEGSRTY ETVFSTVLTP 442- CD2VhhDP SYIMA YEESVKG VYEKFDL 444

[0319] AISYEGSRTY ETVFSTVLTP 445- CD2VhhDQ SLAMA YEESVKG VYEKFDL 447

[0320] AISYEGSRTY ETVFSTVLTP 448- CD2VhhDR ILIMA YEESVKG VYEKFDL 450

[0321] AISYEGSRTY ETVFSTVLTP 451- CD2VhhDS SSIMA YEESVKG VYEKFDL 453

[0322] AISSEGSRTYY ETVFSTVLTP 454- CD2VhhDT SLIMA EESVKG VYEKFDL 456

[0323] AISYEGSRTY EEVFSTVLTP 457- CD2VhhDU SLIMA YEESVKG VYEKFDL 459

[0324] AISYEGSRTY ETLFSTVLTPV 460- CD2VhhDV SLIMA YEESVKG YEKFDL 462 CD2VhhD AISYEGSRTY ETVGSTVLTP 463- W SLIMA YEESVKG VYEKFDL 465

[0325] AISYEGSRTY TVFSTVLTGV 466-

[0326]

[0327] CD2VhhDX SLIMA YEESVKG YEKFDL 468 For the multivalent antibody provided herein, in embodiments, the anti-CD2 antibody region includes a variant of any one of CDRH1, CDRH2. CDR H3, CDRL1, CDR L2, and CDR L3, or a combination thereof.

[0328] In embodiments, the multivalent antibody includes an antibody region including one or more Variable Heavy (VH) sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VH sequences shown in Table 2.

[0329] In embodiments, the multivalent antibody includes an antibody region including one or more Variable Light (VL) sequences that are at least 90% identical (e g., 95%, 99%, or 100% identical) to the VL sequences shown in Table 2.

[0330] In embodiments, the multivalent antibody includes an antibody region including one or more VH sequences that are at least 90% identical (e.g.. 95%. 99%. or 100% identical) to the VH sequences shown in Table 2 and one or more VL sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VL sequences shown in Table 2.

[0331] In embodiments, the multivalent antibody includes an antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 2. e.g., SEQ ID NO: 469, and one VL sequence that is at least 90% identical (e g., 95%, 99%, or 100% identical) to a VL sequence shown in the single row of Table 2, e.g., SEQ ID NO: 470. 062460-503001WQ In embodiments, a multivalent antibody comprising a sequence that is less than 100% identical to a sequence shown in Table 2 comprises one, two or three amino acid mutations which are independently a substitution mutation, a deletion mutation, an insertion mutation, or a combination thereof.

[0332] Table 2 VH and VLs Corresponding to CD2 antigen binding domains

[0333] Name VH Sequence VL Sequence SEQ ID NOs (Left to right) EVQLEESGAELVRPGTSVKLSCKAS DIVMTQAAPSVPVTPGESVSISCRS 469-470 GYTFTSYWMHWIKQRPEQGLEWIG SKTLLHSNGNTYLYWFLQRPGQSP RIDPYDSETHYNEKFKDKAILSVDK QVLIYRMSNLASGVPNRFSGSGSE CD2F SSSTAYIQLSSLTSDDSAVYYCSRRD TTFTLRISRVEAEDVGIYYCMQHL

[0334] abA AKYDGYALDYWGQGTSVTVSS EYPYTFGGGTKLEIE EVQLVESGAELKKPGESLKISCKAS DIVMTQAAPSVPVTPGESVSISCRS 471-472 GYTFTSYWMHWIRQMPGQGLEWIG SKTLLHSNGNTYLYWYLQRPGQSP RIDPYDSETHYNESFQGKATLSVDK QLLIYRMSNLASGVPNRFSGSGSET CD2F SSSTAYLQWSSLKASDTAVYYCSRR TFTLRISRVEAEDVGIYYCMQHLE

[0335] abB DAKYDGYALDYWGQGTLVTVSS YPYTFGGGTKLEIE EVQLVESGAELKKPGESLKISCKAS 473-474 GYTFTSYWMHWVRQMPGQGLEW DIVMTQAAPSVPVTPGESVSISCRS MGRIDPYDSETHYNPSFQGKVTISV SKTLLHSNGNTYLYWYLQRPGQSP DKSSSTAYLQWSSLKASDTAVYYC QLLIYRMSN LASGV P D RFSGSGSG CD2F ARRDAKYDGYALDYWGQGTLVTV TDFTLRISRVEAEDVGIYYCMQHL

[0336] abC SS EYPYTFGGGTKLEIE EVQLEESGAELVRPGTSVKLSCKAS DIVMTQAAPSVPVTPGESVSISCRS 475-476 GYTFTSYWMHWIKQRPEQGLEWIG SKTLLHSNGNTYLYWYLQRPGQSP RIDPYDSETHYNEKFQGKAILSVDK QLLIYRMSNLASGVPDRFSGSGSG CD2F SSSTAYIQLSSLTSDDSAVYYCSRRD TDFTLRISRVEAEDVGIYYCMQHL

[0337] abD AKYDGYALDYWGQGTSVTVSS EYPYTFGGGTKLEIE EVQLVESGAELKKPGESLKISCKAS DIVMTQSPLSLPVTPGEPASISCRSS 477-478 GYTFTSYWMHWIRQMPGQGLEWM KTLLHSNGNTYLYWYLQRPGQSP GRIDPYDSETHYNPSFQGKVTISVDK QLLIYRMSNLASGVPDRFSGSGSG CD2F SSSTAYLQWSSLKASDTAVYYCSRR TDFTLRISRVEAEDVGIYYCMQHL

[0338] abE DAKYDGYALDYWGQGTLVTVSS EYPYTFGQGTKLEIK EVQLEESGAELKKPGESLKISCKASG DIVMTQSPLSLPVTPGEPASISCRSS 479-480 YTFTSYWMHWIKQRPEQGLEWIGRI KTLLHSNGNTYLYWYLQRPGQSP DPYDSETHYNEKFQGKAILSVDKSS QLLIYRMSNLASGVPDRFSGSGSG CD2F STAYLQWSSLKASDTAVYYCSRRD TDFTLRISRVEAEDVGIYYCMQHL

[0339] abF AKYDGYALDYWGQGTLVTVSS EYPYTFGQGTKLEIK EVQLVESGAELKKPGESLKISCKAS DIVMTQAAPSVPVTPGESVSISCRS 481-482 GYTFTSYWMHWIRQMPGQGLEWM SKTLLHSNGNTYLYWYLQRPGQSP GRIDPYDSETHYNPSFQGKVTISVDK QLLIYRMSNLASGVPDRFSGSGSG CD2F SSSTAYLQWSSLKASDTAVYYCSRR TDFTLRISRVEAEDVGIYYCMQHL

[0340] abG DAKYDGYALDYWGQGTLVTVSS EYPYTFGGGTKLEIE EVQLEESGAELVRPGTSVKLSCKAS DIVMTQAAPSVPVTPGESVSISCRS 483-484 GYTFTSYWMHWIKQRPEQGLEWIG SKTLLHSNGNTYLYWYLQRPGQSP RIDPYDSETHYNPSFQGKATLSVDK QLLIYRMSNLASGVPDRFSGSGSG CD2F SSSTAYIQLSSLTSDDSAVYYCSRRD TDFTLRISRVEAEDVGIYYCMQHL

[0341]

[0342] abH AKYDGYALDYWGQGTSVTVSS EYPYTFGGGTKLEIE 062460-503001WG Name VH Sequence VL Sequence SEQ ID NOs (Left to right) EVQLEESGAELVRPGTSVKLSCKAS DIVMTQSPLSLPVTPGEPASISCRSS 485-486 GYTFTSYWMHWIRQMPEQGLEWIG KTLLHSNGNTYLYWYLQRPGQSP RIDPYDSETHYNEKFKDKAILSVDK QLLIYRMSNLASGVPDRFSGSGSG CD2F SSSTAYIQLSSLKASDSAVYYCSRRD TDFTLRISRVEAEDVGIYYCMQHL

[0343] abl AKYDGYALDYWGQGTSVTVSS EYPYTFGQGTKLEIK EVQLVESGAELKKPGESLKISCKAS DIVMTQAAPSVPVTPGESVSISCRS 487-488 GYTFTSYWMHWIRQMPGQGLEWIG SKTLLHSNGNTYLYWYLQRPGQSP RIDPYDSETHWPSFQGKATLSVDK QLLIYRMSNLASGVPNRFSGSGSET CD2F SSSTAYLQWSSLKASDTAVYYCSRR TFTLRISRVEAEDVGIYYCMQHLE

[0344] abJ DAKYDGYALDYWGQGTLVTVSS YPYTFGGGTKLEIE EVQLEESGAELVRPGTSVKLSCKAS DIVMTQAAPSVPVTPGESVSISCRS 489-490 GYTFTSYWMHWIRQMPEQGLEWIG SKTLLHSNGNTYLYWYLQRPGQSP RIDPYDSETHYNEKFKDKAILSVDK QLLIYRMSNLASGVPNRFSGSGSET CD2F SSSTAYIQLSSLKASDSAVYYCSRRD TFTLRISRVEAEDVGIYYCMQHLE

[0345] abK AKYDGYALDYWGQGTSVTVSS YPYTFGGGTKLEIE EVQLQQSGPELQRPGASVKLSCKAS DVVLTQTPPTLLATIGQSVSISCRSS 491-492 GYIFTEYYMYWVKQRPKQGLELVG QSLLHSSGNTYLNWLLQRTGQSPQ RIDPEDGSIDYVEKFKKKATLTADTS PLIYLVSKLESGVPNRFSGSGSGTD CD2F SNTAYMQLSSLTSEDTATYFCARGK FTLKISGVEAEDLGVYYCMQFTHY

[0346] abL FNYRFAYWGQGTLVTVSS PYTFGAGTKLELK QVQLVQSGAEVKKPGASVKVSCKA DVVMTQSPPSLLVTLGQPASISCRS 493-494 SGYTFTEYYMYWVRQAPGQGLEL SQSLLHSSGNTYLNWLLQRPGQSP MGRIDPEDGSIDYVEKFKKKVTLTA QPLIYLVSKLESGVPDRFSGSGSGT CD2F DTSSSTAYMELSSLTSDDTAVYYCA DFTLKISGVEAEDVGVYYCMQFTH

[0347] abM RGKFNYRFAYWGQGTLVTVSS YPYTFGQGTKLEIK QVQLQQPGTELVRPGSSVKLSCKAS DIVMTQSPATLSVTPGDRVSLSCR 495-496 CD2F GYTFTSY WVNW VKQRPDQGLEWIG ASQSISDYLHWYQQKSHESPRLLIK

[0348] abN RIDPYDSETHYNQKFTDKAISTIDTS YASQSISGIPSRFSGSGSGSDFTLSI SNTAYMQLSTLTSDASAVYYCSRSP NSVEPEDVGVYYCQNGHSFPLTFG

[0349]

[0350] RDSSTNLADWGQGTLVTVSS AGTKLELR

[0351] An scFV comprises a VL domain and an VH domain connected by a linker. For any of the anti-CD2 scFvs useful in the present disclosure, the orientation can be any anti-CD2 VH domain as disclosed herein (e.g., from Table 2) - any linker as disclosed herein (e.g., from Table 10) - any anti-CD2 VL domain as disclosed herein (e.g., from Table 2) or can be any anti-CD2 VL domain as disclosed herein - any linker as disclosed herein (e.g., from Table 10) - any anti-CD2 VH domain as disclosed herein.

[0352] In embodiments, the multivalent antibody includes a single domain antibody region including one or more VHH sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VHH sequences shown in Table 3.

[0353] In embodiments, the multivalent antibody includes a single domain antibody region including one or more VHH sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VHH sequences shown in Table 3. 062460-503001WG In embodiments, the multivalent antibody includes a single domain antibody region including a VHH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VHH sequence show n in a single row of Table 3, e.g., SEQ ID NO: 497.

[0354] In embodiments, a multivalent antibody comprising a sequence that is less than 100% identical to a sequence shown in Table 3 comprises one, two or three amino acid mutations which are independently a substitution mutation, a deletion mutation, an insertion mutation, or a combination thereof.

[0355] Any of the VHH sequences of Table 3 can be provided absent a constant region, e.g., an Fc domain.

[0356] Table 3 VHHs Corresponding to CD2 antigen binding domains

[0357] Name VHH Sequence SEQ ID NOs (Left to nght) CD2VhhA EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 497 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhB EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 498 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhC EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 499 SVAAISYIGSRTYYEESVKGRFTISRDNAKKVMYLQMNSLKPEDTA VYYCAGDTVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhD EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 500 SVAAISYIGSRTYYEESVKGRFTISRDNAKKVMYLQMNSLKPEDTA VYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhE EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 501 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVMTPVYEKFDLWGQGTLVTVSS CD2VhhF EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 502 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVMTPVYEKFDLWGQGTLVTVSS CD2VhhG EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVR 503 ESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhH EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVR 504 ESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhI EVQLVESGGGLVQPGGSLRLSCAASGRAFTTYAVGWFRQHPGKE 505 REFVTAISTGGGDTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPE DTAVYTCAAAPWLHLTSYWGTWAEYDTWGQGTLVTVSS CD2VhhJ EVQLVESGGGLVQPGGSLRLSCAASGRAFTTYAVGWFRQHPGKE 506

[0358] REFVTAISTGGGDTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPE

[0359]

[0360] DTAVYTCAAAPWLHLTSYYGTWAEYDTWGQGTLVTVSS Name VHH Sequence SEQ ID NOs (Left to nght) CD2VhhK EVQLVESGGGLVQPGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 507 ESVAAISYLGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYC AGDTVFSTVMTP VYEKFDL WGQGTLVTV S S CD2VhhL EVQLVESGGGLVQPGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 508 ESVAAISYLGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYC AGETVF STVMTPVYEKFDLWGQGTLVTVS S CD2VhhM EVQLVESGGGLVQPGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 509 ESVAAISYLGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGETVFSTVLTP VYEKFDL WGQGTLVTVSS CD2VhhN EVQLVESGGGLVQPGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 510 ESVAAISYLGSRTYYEESVKGRFTISRDNAKDTVYLQMNSLKPEDT AVYYC AGETVF STVMTPVYEKFDLWGQGTLVTVS S CD2VhhO EVQLVESGGGLVQPGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 511 ESVAAISYLGSRTYYEESVKGRFTISRDNAKDTVYLQMNSLKPEDT AVYYCAGETVFSTVLTP VYEKFDL WGQGTLVTVSS CD2VhhP EVQLVESGGGLVQPGGSLRLSCAASGQTFSLYAVGWFRQAPGKER 512 EFVTAISTGGGDTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPEDT AVYTCAAAPWLHLTSYWGTWAEYDTWGQGTLVTVSS CD2VhhQ EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKERE 513 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVLTPVAEKFDL WGQGTLVTVSS CD2VhhR EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKERE 514 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhS EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKERE 515 SVAAISYIGSRTYYEESVKGRFTISRDNAKDTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVAEKFDL WGQGTLVTVSS CD2VhhT EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 516 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVVTPAYEKFDLWGQGTLVTVSS CD2VhhU EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 517 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVVTPAYEKFDL WGQGTLVTVSS CD2VhhV EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 518 SVAAISYIGSRTYYEESVKGRFTISRDNAKDTVYLQMNSLKPEDTA VYYCAGETVFSTVVTPAYEKFDLWGQGTLVTVSS CD2VhhW EVQLVESGGGLVQPGGSLRLSCAASGRDFTTYAVGWFRQAPGKE 519 REFVTAISTGGGSTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPED TAVYTCAAAPWLHLTSYWGTWSEYDTWGQGTLVTVSS CD2VhhX EVQLVESGGGLVQPGGSLRLSCAASGRDFTTYAVGWFRQAPGKE 520 REFVTAISTGGGSTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPED TAVYTCAAAPWLHLTSYYGTWSEYDTWGQGTLVTVSS CD2VhhY EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 521 SVAAISYIGSRTYYEESVKGRFTISRDNAENTVYLQMNSLKPEDTA VYYCAGDTVFSTILTPVYDKFDLWGQGTLVTVSS CD2VhhZ EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 522

[0361] SVAAISYIGSRTYYEESVKGRFTISRDNAENTVYLQMNSLKPEDTA

[0362]

[0363] VYYCAGETVFSTILTPVYDKFDLWGQGTLVTVSS Name VHH Sequence SEQ ID NOs (Left to nght) CD2VhhAA EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGTERE 523 SVAAISYDGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSAVMTPVAEQFDLWGQGTLVTVSS CD2VhhAB EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGTERE 524 SVAAISYDGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYC AGETVF S AVMTP VAEQFDL WGQGTLVTVS S CD2VhhAC EVQLVESGGGLVQPGGSLRLSCAASGRTISNLIMAWFRQTPGKERE 525 SVAAISYDGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFAAVMTPVAEQFDLWGQGTLVTVSS CD2VhhAD EVQLVESGGGLVQPGGSLRLSCAASGRTISNLIMAWFRQTPGKERE 526 SVAAISYDGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGETVFAAVMTPVAEQFDLWGQGTLVTVSS CD2VhhAE EVQLVESGGGLVQPGGSLRLSCAASGRDFTTYAVGWFRQAPGKG 527 REFVTAISTGGGDTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPE DTAVYTCAAAPWLRLTSYWGTWSEYDTWGQGTLVTVSS CD2VhhAF EVQLVESGGGLVQPGGSLRLSCAASGRDFTTYAVGWFRQAPGKG 528 REFVTAISTGGGDTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPE DTAVYTCAAAPWLRLTSYYGTWSEYDTWGQGTLVTVSS CD2VhhAG EVQLVESGGGLVQPGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 529 ESVAAISYLGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhAH EVQLVESGGGLVQPGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 530 ESVAAISYLGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhAI EVQLVESGGGLVQPGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 531 ESVAAISYLGSRTYYEESVKGRFTISRDNAKDTVYLQMNSLKPEDT AVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhAJ EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 532 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFAAVMTPVAEQFDLWGQGTLVTVSS CD2VhhAK EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 533 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFAAVMTPVAEQFDLWGQGTLVTVSS CD2VhhAL EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 534 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFAAVLTPVAEQFDLWGQGTLVTVSS CD2VhhAM EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 535 SVAAISYIGSRTYYEESVKGRFTISRDNAKDTVYLQMNSLKPEDTA VYYCAGETVFAAVMTPVAEQFDLWGQGTLVTVSS CD2VhhAN EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 536 SVAAISYIGSRTYYEESVKGRFTISRDNAKDTVYLQMNSLKPEDTA VYYCAGETVFAAVLTPVAEQFDLWGQGTLVTVSS CD2VhhA0 EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 537 SVAAISYDGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhAP EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 538

[0364] SVAAISYDGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT

[0365]

[0366] AVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS Name VHH Sequence SEQ ID NOs (Left to nght) CD2VhhAQ EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 539 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVMTPKYEKFDLWGQGTLVTVSS CD2VhhAR EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 540 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVMTPKYEKFDLWGQGTLVTVSS CD2VhhAS QVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 541 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhAT QVKLEESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 542 SVAAISYIGSRTYYEESVKGRFTISRDNAKKVMYLQMNSLKPEDTA VYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhAU EVQLVESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 543 CVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVMTPVYEKFDLWGQGTLVTVSS CD2VhhAV EVQLVESGGGLVQAGGSLRLSCAASGRTISGLIMAWFRQTPGKVR 544 ECVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhAW QVKLEESGGGLVQAGGSLRLSCTASGRAFTTYAVGWFRQHPGKE 545 REFVTAISTGGGDTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPE DTAVYTCAAAPWLHLTSYWGTWAEYDTRGQGTQVTVSS CD2VhhAX EVQLVESGGGLVQHGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 546 ECVAAISYLGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVMTPVYEKFDLWGQGTQVTVSS CD2VhhAY EVQLVESGGGLVQAGGSLRLSCTASGQTFSLYAVGWFRQAPGKE 547 REFVTAISTGGGDTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPE DTAVYTCAAAPWLHLTSYWGTWAEYDTRGQGTQVTVSS CD2VhhAZ QVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKER 548 ECVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhBA QVKLEESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 549 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVVTPAYEKFDLWGQGTQVTVSS CD2VhhBB QLQLVESGGGLVQAGGSLRLSCAASGRDFTTYAVGWFRQAPGKE 550 REFVTAISTGGGSTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPED TAVYTCAAAPWLHLTSYWGTWSEYDTRGQGTQVTVSS CD2VhhBC EVQLEESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 551 SVAAISYIGSRTYYEESVKGRFTISRDNAENTVYLQMNSLKPEDTA VYYCAGDTVFSTILTPVYDKFDLWGQGTQVTVSS CD2VhhBD QVKLEESGGGLVQAGGSLRLSCAASGRTISGLIMAWFRQTPGTER 552 ECVAAISYDGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPED TAVYYCAGDTVFSAVMTPVAEQFDLWGQGTQVTVSS CD2VhhBE QVKLEESGGGLVQAGGSLRLSCAASGRTISNLIMAWFRQTPGKER 553 ECVAAISYDGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPED TAVYYCAGDTVFAAVMTPVAEQFDLWGQGTLVTVSS CD2VhhBF EVQLVESGGGLVQAGGSLRLSCAASGRDFTTYAVGWFRQAPGKG 554

[0367] REFVTAISTGGGDTYYLDSVKGRFTISRDNTKNTVYLQMNSLKPE

[0368]

[0369] DTAVYTCAAAPWLRLTSYWGTWSEYDTRGQGTQVTVSS Name VHH Sequence SEQ ID NOs (Left to nght) CD2VhhBG QVKLEESGGGLVQAGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 555 ECVAAISYLGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhBH QVKLEESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 556 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFAAVMTPVAEQFDLWGQGTQVTVSS CD2VhhBI QVKLEESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 557 CVAAISYDGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVLTPVYEKFDLWGQGTQVTVSS CD2VhhB3 QLQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 558 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVMTPKYEKFDLWGQGTQVTVSS CD2VhhBK QVQLVQSGGGQAQAGGSLRLSCLVSGQPLSTYAMGWFRQAPGKE 559 REFVASAGNWNDHTIYADSVKDRFTISRDNAKNTVYLQMNSLKV EDTAIYYC AAN AV AS ATTPQYNYWGQGTQ VTV S S CD2VhhBL QVKLEESGGGLVQPGGSLRLSCAVSGSMVRINTMGWFRQAPGKG 560 REFVADLSWRFDDIGYADSVKGRFTISRDNAKKVMYLQMNSLKP EDTAIYYCAADKNFDLPSTWQSIDYWGQGTQVTVSS CD2VhhBM QVQLVESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKER 561 ESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhBN QVKLEESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 562 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhB0 QVKLEESGGGLVQAGGSLRLSCAASGRTISNLIMAWFRQTPGKER 563 ECVAAISCIGSRTYYEESVKGRFTISRDNAKKVMYLQMNSLKPDD TAVYYCAADTRVRIYAYTDPTWYDYWGQGTQVTVSS CD2VhhBP QVKLEESGGDFVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 564 CVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVMTPVYEKFDLWGQGTQVTVSS CD2VhhBQ EVQLEESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 565 CVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhBR QVKLEESGGGLVQAGGSLRLSCAASGRDFTTYAVGWFRQHPGKE 566 REFVTAISTGGGDTYYLDSVKGRFTISRDNAKKVMYLQMNSLKPE DTAIYYCAADKNFDLPSTWQSIDYWGQGTQVTVSS CD2VhhBS EVQLVESGGGLVQPGGSLRLSCAVSGSMVRINTMGWFRQAPGKG 567 REFVADLSWRFDDIGYADSVKGRFTISRDNAKKVMYLQMNSLKP EDTAIYYCAADKNFXLPSTWQSIDYWGQGTQVTVSS CD2VhhBT EVQLVESGGGLVQPGGSLRLSCAVSGSMVRINTMGWFRQAPGKG 568 REFVADLSWRFDDIGYADSVKGRFTISRDNTKNTVYLQMNSLKPE DTAVYTCAAAPWLHLTSYWGTWSEYSTRGQGTLVTVSS CD2VhhBU QVKLVESGGGLVQVGGSLRLSCAASGRTISSLIMAWFRQTPGKER 569 ESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhBV QVKLVESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKER 570

[0370] ESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT

[0371]

[0372] AVYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS Name VHH Sequence SEQ ID NOs (Left to right) CD2VhhBW QVQLVESGGGLVQAGGSLRLSCAASANILSFNVMGWYRQAPGKG 571 REFVADLSWRFDDIGYADSVKGRFTISRDNAKKVMYLQMNSLKP EDTAIYYCAADKNFDLPSTWQSIDYWGQGTQVTVSS CD2VhhBX QVQLVESGGGLVQPGGSLRLSCAVSGSMVRINTMGWFRQAPGKG 572 REFVADLSWRFDDIGYADSVKGRFTISRDNAKKVMYLQMNSLKP EDTAVYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhBY EVQLVESGGGLVQPGGSLRLSCAVSGSMVRINTMGWFRQAPGKG 573 REFVADLSWRFDDIGYADSVKGRFTISRDNAKKVMYLQMNSLKP EDTAIYYCAADKNFDLPSTWQSIDYWGQGTQVTVSS CD2VhhBZ QVKLEESGGGLVQAGGSLRLSCAVSGSMVRINTMGWFRQAPGKG 574 REFVADLSWRFDDIGYADSVKGRFTISRDNAKKVMYLQMNSLKP EDTAIYYCAADKNFDLPSTWQSIDYWGQGTQVTVSS CD2VhhCA QVKLEESGGGLVQPGGSLRLSCAVSGSMVRINTMGWFRQAPGKG 575 REFVADLSWRFDDIGYADSVKGRFTISRDNAKKVMYLQMNSLKP EDTAIYYCAAVITAGSFTVRCPLGVPHLYDYWGQGTQVTVSS CD2VhhCB QVKLEESGGGLVQPGGSLRLSCAVSGSMVRINTMGWFRQAPGKG 576 REFVADLSWRFDDIGYADSVKGRFTISRDNAKKVMYLQMNSLKP EDTAIYYCAADKNFDLPSTWQSIDYWGQGTXVTVSS CD2VhhCC QVKLEESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 577 CVAAISYDGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVVTPAYEKFDLWGQGTQVTVSS CD2VhhCD QLQLVESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 578 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhCE EVQLVESGGGLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 579 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhCF EVQLEESGGGLVQAGGSLRLSCAASGRTISGLIMAWFRQTPGKER 580 ECVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVLTPVAEKFDLWGQGTQVTVSS CD2VhhCG QLQLVESGGNLVQAGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 581 SVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGDTVFSTVLTPVAEKFDLWGQGTLVTVSS CD2VhhCH QVKLEESGGGLVQAGGSLRLSCAASGRTIDNLIMAWFRQTPGKER 582 ECVAAISYLGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGDTVFSTVMTPVYEKFDLWGQGTQVTVSS CD2VhhCI EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 583 S VAAIS YSGSRTYYEES VKGRF TISRDN AKNTVYLQMN SLKl’EDTA VYYCAGETVFSTVLTPWEKFDLWGQGTLVTVSS CD2VhhC3 EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 584 SVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAKETVFSWLTPXYTKFDLWGQGTLVTVSS CD2VhhCK EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 585 S VAAIS YSGSRTYYEES VKGRF TISRDNAKNTVYLQMNSLKl’EDTA VWCAGEAVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhCL EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 586

[0373] SVAAISYSGSRTYYEESVKGRFTISRDNAKNT'VYLQMNSLKPEDTA

[0374]

[0375] VYYCAGETAFSTVLTPVYEKFDLWGQGTLVTVSS Name VHH Sequence SEQ ID NOs (Left to right) CD2VhhCM EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 587

[0376] SVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA V YYC AGETV AST VLTP V YEKFDL W GQGTLV TV S S CD2VhhCN EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 588

[0377] SVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLAPVYEKFDLWGQGTLVTVSS CD2VhhC0 EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 589

[0378] SVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTAVYERFDLWGQGTLVTVSS CD2VhhCP EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 590

[0379] SVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEYFDLWGQGTLVTVSS CD2VhhCQ EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 591

[0380] SVAAISGSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhCR EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 592

[0381] SVAAISYSGGRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhCS EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 593

[0382] SVAAISYSGSSTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhCT EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 594

[0383] SVAAISYSGSRTYYAESVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhCU EVQLVESGGGLVQPGGSLRLSCAASGRTISSYIMAWFRQTPGKERE 595

[0384] SVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhCV EVQLVESGGGLVQPGGSLRLSCAASGRTISSLAMAWFRQTPGKER 596

[0385] ESVAAISYSGSRTYYEESVKGRFTISRDN AKNTVYLQMNSLKPEDT AVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhCW EVQLVESGGGLVQPGGSLRLSCAASGRTISILIMAWFRQTPGKERE 597

[0386] S VAAIS YSGSRTYYEESVKGRF TISRDN AKNTVYLQMN SLKl’EDTA VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhCX EVQLVESGGGLVQPGGSLRLSCAASGRTISSSIMAWFRQTPGKERE 598

[0387] SVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhCY EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 599

[0388] S VAAISSSGSRTYYEESVKGRFTISRDNAKN TVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhCZ EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 600

[0389] SVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGEEVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDA EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 601

[0390] S VAAIS YSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKl’EDTA VWCAGETLFSWLTPVYEKFDLWGQGTLVTVSS CD2VhhDB EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 602

[0391] SVAAISYSGSRTYYEESVKGRFTISRDNAKNT'VYLQMNSLKPEDTA

[0392]

[0393] VYYCAGETVGSTVLTPVYEKFDLWGQGTLVTVSS Name VHH Sequence SEQ ID NOs (Left to right) CD2VhhDC EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 603 SVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA V YYC AGETV F ST VLTGV YEKFDL W GQGTL V TV S S CD2VhhDD EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 604 SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDE EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 605 SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAKETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDF EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 606 SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGEAVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDG EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 607 SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETAFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDH EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 608 SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVASTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDI EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 609 SVAAISYEGSRTY^7EESVKGRFTISRDNAKNTVYLQ]VINSLKPEDTA VYYCAGETVFSTVLAPVYTKFDLWGQGTLVTVSS CD2VhhD3 EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 610 SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTAVYEKFDLWGQGTLVTVSS CD2VhhDK EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 611 SVAAISYEGSRTY^7EESVKGRFTISRDNAKNTVYLQ]VINSLKPEDTA VYYCAGETVFSTVLTPVYEYFDLWGQGTLVTVSS CD2VhhDL EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 612 SVAAISGEGSR1YYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDM EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 613 SVAAISYEGGRIYYEESVKGRFTISRDNAKNT'VYLQMNSLKPEDT AVWCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDN EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 614 SVAAISYEGSSTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhD0 EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 615 SVAAISYEGSRTYYAESVKGRFTISRDNAKNTVYLQMNSLKl’EDT AVWCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDP EVQLVESGGGLVQPGGSLRLSCAASGRTISSYIMAWFRQTPGKERE 616 SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDQ EVQLVESGGGLVQPGGSLRLSCAASGRTISSLAMAWFRQTPGKER 617 ESVAAISYEGSRIYYEESVKGRFTISRDNAKNTVYLQMNSLKI’EDT AVWCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDR EVQLVESGGGLVQPGGSLRLSCAASGRTISILIMAWFRQTPGKERE 618

[0394] SVAAISYEGSR1YYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA

[0395]

[0396] VYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSS 062460-503001WG Name VHH Sequence SEQ ID NOs (Left to nght) CD2VhhDS EVQLVESGGGLVQPGGSLRLSCAASGRTISSSIMAWFRQTPGKERE 619

[0397] SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA V YYC AGETV I S E VLTP VYEKFDL W GQGTL VTV S S CD2VhhDT EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 620

[0398] SVAAISSEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVFSTVLTPVYEKFDL WGQGTLVTVSS CD2VhhDU EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 621

[0399] SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGEEVFSTVLTP VYEKFDL WGQGTLVTVSS CD2VhhDV EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 622

[0400] SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETLFSTVLTPVYEKFDLWGQGTLVTVSS CD2VhhDW EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 623

[0401] SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAGETVGSTVLTPVYEKFDL WGQGTLVTVSS CD2VhhDX EVQLVESGGGLVQPGGSLRLSCAASGRTISSLIMAWFRQTPGKERE 624

[0402] SVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTA

[0403]

[0404] VYYCAGETVFSTVLTGVYEKFDLWGQGTLVTVSS

[0405] In embodiments, a multivalent antibody including a sequence that is less than 100% identical to a sequence show n in one or more of Table 1 to Table 3 retains affinity for CD2 that is substantially equivalent to a multivalent antibody including a sequence that is 100% identical to a sequence shown in one or more of Table 1 to Table 3.

[0406] In embodiments, a multivalent antibody including a sequence that is less than 100% identical to a sequence shown in one or more of Table 1 to Table 3 has less affinity’ for CD2 than a multivalent antibody including a sequence that is 100% identical to a sequence shown in one or more of Table 1 to Table 3.

[0407] PD-1

[0408] In embodiments, the multivalent antibody includes an antibody region including one to six complementarity determining regions (" CDRs") sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the CDR sequence shown in Table 4 or Table 5.

[0409] In embodiments, the multivalent antibody includes a single domain antibody region including three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) sequences from a single row of Table 4, e.g., SEQ ID NO: 625 to SEQ ID NO: 627.

[0410] In embodiments, the multivalent antibody includes an antibody region including three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) sequences from a single row of Table 4, e.g., SEQ ID NO: 718 to SEQ ID NO: 720. 062460-503001WQ In embodiments, the multivalent antibody includes an antibody region including three Light Chain CDRs (CDR-L1, CDR-L2, and CDR-L3) sequences from a single row of Table 5, e g., SEQ ID NO: 721 to SEQ ID NO: 723.

[0411] In embodiments, the multivalent antibody includes an antibody region including CDR-H1, CDR-H2. CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences from a single row of Table 5, e.g., SEQ ID NO: 718 to SEQ ID NO: 723.

[0412] In embodiments, a multivalent antibody comprising a sequence that is less than 100% identical to a sequence shown in Table 4 or Table 5 comprises one, two or three amino acid mutations which are independently a substitution mutation, a deletion mutation, an insertion mutation, or a combination thereof.

[0413] Table 4 CDRs Corresponding to PD-1 VHH antigen binding domains

[0414] Name CDR-H1 CDR-H2 CDR-H3 SEQ

[0415] ID NOs (Left to right ) PDIVhhA SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 625-627 PDIVhhB SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 628-630 PDIVhhC SYHMG 631-63 AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 3 PDIVhhD SYHMG 634-63 AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 6 PDIVhhE SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 637-639 PDIVhhE SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 640-642 PDIVhhG SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 643-645 PDIVhhH SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 646-648 PDIVhhl SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 649-651 PDIVhhJ SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 652-654 PDIVhhK SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 655-657 PDIVhhL SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 658-660 PDIVhhM SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 661-663 PDIVhhN SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 664-666 PDIVhhO SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 667-669 PDIVhhP SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 670-672 PDIVhhQ SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 673-675 PDIVhhR SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 676-678 PDIVhhS SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 679-681 2xPDlVhhA SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 682-684 2xPDlVhhB SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 685-687 2xPDlVhhC SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 688-690 2xPDlVhhD SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 691-693

[0416]

[0417] 2xPDlVhhE GYGIV VISSDGTTNYGDSVRG PIGGTWN 694-696 062460-503001WG 2xPDlVhhF GYGIV VISSDGTTNYGDSVRG PIGGTWN 697-699 2xPDlVhhG SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 700-702 2xPDlVhhH SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 703-705 2xPDlVhhl SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 706-708 2xPDlVhhJ SYHMG AIPRSGSNIGYSAFVKD KSAAGYYSGVVFTADYDYTY 709-711 2xPDlVhhK GYGIV VISSDGTTNYGDSVRG PIGGTWN 712-714

[0418]

[0419] 2xPDlVhhL GYGIV VISSDGTTNYGDSVRG PIGGTWN 715-717

[0420] Table 5 CDRs Corresponding to PD1 antigen binding domains

[0421] Name CDR-H1 CDR-H2 CDR-H3 CDR-L1 CDR-L2 CDR-L3 SEQ ID Nos (Left to right) WIYPGSV 718-723 YSNWFFD RASQEISG LQYASYP PDIFab NTKYNEK

[0422] A Y I V YLS AASTLDS D Y N FRG YT GINPSNGG RASKGVS 724-729 PDIFab TNFNEKF RDYRFDM QHSRDLP

[0423] GFDY TSGYSYL LASYLES B NYYMY KN H LT VIWYDGS RASQSV 730-735 PDIFab KRYYADS NDDY SS DASNR QQSSNWPAT

[0424] YLA RT C NSGMH VKG

[0425]

[0426] In embodiments, the multivalent antibody includes an antibody region including one or more Variable Heavy (VH) sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VH sequences shown in Table 6.

[0427] In embodiments, the multivalent antibody includes an antibody region including one or more Variable Light (VL) sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VL sequences shown in Table 6.

[0428] In embodiments, the multivalent antibody includes an antibody region including one or more VH sequences that are at least 90% identical (e.g., 95%, 99%. or 100% identical) to the VH sequences shown in Table 6 and one or more VL sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VL sequences shown in Table 6.

[0429] In embodiments, the multivalent antibody includes an antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 6 and one VL sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VL sequence show n in the single row of Table 6, e.g., SEQ ID NO: 736 and SEQ ID NO: 737.

[0430] In embodiments, a multivalent antibody comprising a sequence that is less than 100% identical to a sequence shown in Table 6 comprises one. two or three amino acid mutations which are independently a substitution mutation, a deletion mutation, an insertion mutation, or a combination thereof. 062460-503001WG Table 6 VH and VLs Corresponding to PD1 antigen binding domains

[0431] Name VH Sequence VL Sequence SEQ ID NOs (Left to right) PDIFabA QIQLQQSGPELVKPGASVKISCK DIVMTQSPSSLSASLGERVSL 736-737

[0432] ASGYTFTDYYINWVKQKPGQG TCRASQEISGYLSWLQQKPD LEWIGWIYPGSVNTKYNEKFRG GTIKRLIYAASTLDSGVPKRF KATLTVDTS S STAYIQLSGLTSE SGSRSGSDYSLSISSLESEDFA DTAVYFCARYSNWFFDVWGA DYYCLQYASYPYTFGGGTKL GTAVTVSS EIK PDIFabB QVQLVQSGVEVKKPGASVKVS EIVLTQSPATLSLSPGERATLS 738-739

[0433] CKASGYTFTNYYMYWVRQAP CRASKGVSTSGYSYLHWYQ GQGLEWMGGINPSNGGTNFNE QKPGQAPRLLIYLASYLESGV KFKNRVTLTTDSSTTTAYMELK PARFSGSGSGTDFTLTISSLEP SLQFDDTAVYYCARRDYRFDM EDFAVYYCQHSRDLPLTFGG GFDYWGQGTTVTVS S GTKVEIK PDIFabC QVQLVESGGGVVQPGRSLRLD EIVLTQSPATLSLSPGERATLS 740-741

[0434] CKASGITFSNSGMHWVRQAPG CRASQSVSSYLAWYQQKPG KGLEWVAV1WYDGSKRYYADS QAPRLL1YDASNRATG1PARF VKGRFTISRDNSKNTLFLQMNS SGSGSGTDFTLTISSLEPEDFA LRAEDTAVYYCATNDDYWGQ VYYCQQSSNWPRTFGQGTK

[0435]

[0436] GTLVTVSS VEIK

[0437] An scFV comprises a VL domain and an VH domain connected by a linker. For any of the anti-PD-1 scFvs useful in the present disclosure, the orientation can be any anti-PD-1 VH domain as disclosed herein (e.g., from Table 6) - any linker as disclosed herein (e.g., from Table 10) - any anti-PD-1 VL domain as disclosed herein (e.g., from Table 6) or can be any anti-PD-1 VL domain as disclosed herein - any linker as disclosed herein (e.g., from Table 10) - any anti-PD-1 VH domain as disclosed herein

[0438] In embodiments, the multivalent antibody includes a single domain antibody region including one or more VHH sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VHH sequences show n in Table 7.

[0439] In embodiments, the multivalent antibody includes a single domain antibody region including one or more VHH sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VHH sequences shown in Table 7.

[0440] In embodiments, the multivalent antibody includes a single domain antibody region including a VHH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VHH sequence shown in a single row of Table 7, e.g., SEQ ID NO: 742.

[0441] In embodiments, a multivalent antibody comprising a sequence that is less than 100% identical to a sequence shown in Table 7 comprises one, two or three amino acid mutations which are independently a substitution mutation, a deletion mutation, an insertion mutation, or a combination thereof. 062460-503001WG Any of the VHH sequences of Table 7 can be provided absent a constant region, e.g., an Fc domain.

[0442] Table 7 VHH Corresponding to PD-1 antigen binding domains

[0443] Name VHH Sequence SEQ ID NO PDIVhhA EVQLVESGGGLVQAGDSLRLSCVASGRTFSSYHMGWFRQAPGKE 742

[0444] REFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLAPDDT AVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSS PDIVhhB EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 743

[0445] GKGLEFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSS PDIVhhC EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 744

[0446] GKGLEFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTL VTVSS PDIVhhD EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 745

[0447] GKGREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSS PDIVhhE EVQLVESGGGLVQPGGSLRLSCVASGRTFSSYHMGWFRQAP 746

[0448] GKGLEFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSS PDIVhhF EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 747

[0449] GKGREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTL VTVSS PDIVhhG EVQLVESGGGLVQPGGSLRLSCVASGRTFSSYHMGWFRQAP 748

[0450] GKGLEFVAAIPRSGSNTGYSAFVKDRGTTSRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTL VTVSS PDIVhhH EVQLVESGGGLVQPGGSLRLSCVASGRTFSSYHMGWFRQAP 749

[0451] GKGREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSS PDIVhhl EVQLVESGGGLVQPGGSLRLSCVASGRTFSSYHMGWFRQAP 750

[0452] GKGREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTL VTVSS PDIVhhJ EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 751

[0453] GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTL VTVSS PDIVhhK EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 752

[0454] GKGREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTL VTVSS PDIVhhL EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 753

[0455] GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM

[0456]

[0457] Name VHH Sequence SEQ ID NO NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSS PDIVhhM EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 754

[0458] GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGAYSGVVFTADYDYTYWGQGTL VTVSS PDIVhhN EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 755

[0459] GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYASGVVFTADYDYTYWGQGTL VTVSS PDIVhhO EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 756

[0460] GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGAVFTADYDYTYWGQGTL VTVSS PDIVhhP EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 757

[0461] GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGVAFTADYDYTYWGQGTL VTVSS PDIVhhQ EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 758

[0462] GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGVVFTAAYDYTYWGQGTL VTVSS PDIVhhR EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 759

[0463] GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGVVFTADYAYTYWGQGTL VTVSS PDIVhhS EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 760

[0464] GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQIN NLRPDDTAVYYCAAKSAAGYYSGVVFTAAYAYTYWGQGTL VTVSS

[0465] 2xPDlVhhA EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 761

[0466] GKGREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSSEPKSADKTHTCPPCPAPEFEGGPSVFLFPPKPKDTL MISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSEVQLV ESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKGRE FVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQMNNLRP DDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTV SS

[0467] 2xPDlVhhB EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 762

[0468] GKGREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSSEPKSADKTHTCPPCPAPEFEGGPSVFLFPPKPKDTL MISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE

[0469]

[0470] KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS Name VHH Sequence SEQ ID NO DIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP GKGREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSS

[0471] 2xPDlVhhC EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 763

[0472] GKGLEFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSSEPKSADKTHTCPPCPAPEFEGGPSVFLFPPKPKDTL MISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSEVQLV ESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKGLE FVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQMNNLRP DDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTV SS

[0473] 2xPDlVhhD EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 764

[0474] GKGLEFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSSEPKSADKTHTCPPCPAPEFEGGPSVFLFPPKPKDTL MISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP GKGLEFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSS

[0475] 2xPDlVhhE EVHLVESGGGLVQAGGSLRLSCVASGSTFSGYGIVWHRQRP 765

[0476] GKQRELVAVISSDGTTNYGDSVRGRFTISRDNAKNTLYLQM NSLEPEDTAVYYCGIPIGGTWNWGQGTQVTVSSEPKSADKT HTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVAV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGGGGSEVHLVESGGGLVQAGGSLRL SCVASGSTFSGYGIVWHRQRPGKQRELVAVISSDGTTNYGDS VRGRFTISRDNAKNTLYLQMNSLEPEDTAVYYCGIPIGGTWN WGQGTQVTVSS

[0477] 2xPDlVhhF EVHLVESGGGLVQAGGSLRLSCVASGSTFSGYGIVWHRQRP 766

[0478] GKQRELVAVISSDGTTNYGDSVRGRFTISRDNAKNTLYLQM NSLEPEDTAVYYCGIPIGGTWNWGQGTQVTVSSEPKSADKT HTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVAV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL

[0479]

[0480] TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ Name VHH Sequence SEQ ID NO VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGGGGSGGGGSEVHLVESGGGLVQAG GSLRLSCVASGSTFSGYGIVWHRQRPGKQRELVAVISSDGTT NYGDSVRGRFTISRDNAKNTLYLQMNSLEPEDTAVYYCGIPI GGTWNWGQGTQVTVSS

[0481] 2xPDlVhhG EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 767

[0482] GKGREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLSCVASGFTFS SYHMGWFRQAPGKGREFVAAIPRSGSNIGYSAFVKDRGTISR DNAKNTVYLQMNNLRPDDTAVYYCAAKSAAGYYSGVVFT ADYDYTYWGQGTLVTVSSEPKSADKTHTCPPCPAPEFEGGPS VFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0483] 2xPDlVhhH EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 768

[0484] GKGREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCVA S GFTFS S YHMGWFRQAPGKGREFV AAIPRS GSNIGYS AFVKD RGTISRDNAKNTVYLQMNNLRPDDTAVYYCAAKSAAGYYS GVVFTADYDYTYWGQGTLVTVSSEPKSADKTHTCPPCPAPE FEGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPG

[0485] 2xPDlVhhI EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 769

[0486] GKGLEFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLSCV AS GFTFS SYHMGWFRQAPGKGLEFVAAIPRSGSNIGYSAFVKDRGTISR DNAKNTVYLQMNNLRPDDTAVYYCAAKSAAGYYSGVVFT ADYDYTYWGQGTLVTVSSEPKSADKTHTCPPCPAPEFEGGPS VFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0487] 2xPDlVhhJ EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP 770

[0488] GKGLEFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQM NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQG TLVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCVA S GFTFS SYHMGWFRQAPGKGLEFV AAIPRS GSNIGYS AFVKD RGTISRDNAKNTVYLQMNNLRPDDTAVYYCAAKSAAGYYS

[0489]

[0490] GVVFTADYDYTYWGQGTLVTVSSEPKSADKTHTCPPCPAPE 062460-503001WG Name VHH Sequence SEQ ID NO FEGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPG

[0491] 2xPDlVhhK EVHLVESGGGLVQAGGSLRLSCVASGSTFSGYGIVWHRQRP 771

[0492] GKQRELVAVISSDGTTNYGDSVRGRFTISRDNAKNTLYLQM NSLEPEDTAVYYCGIPIGGTWNWGQGTQVTVSSGGGGSEVH LVESGGGLVQAGGSLRLSCVASGSTFSGYGIVWHRQRPGKQ RELVAVISSDGTTNYGDSVRGRFTISRDNAKNTLYLQMNSLE PEDTAVYYC GIPIGGTWNWGQGTQVTVS SEPKS ADKTHTCPP CPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG

[0493] 2xPDlVhhL EVHLVESGGGLVQAGGSLRLSCVASGSTFSGYGIVWHRQRP 772

[0494] GKQRELVAVISSDGTTNYGDSVRGRFTISRDNAKNTLYLQM NSLEPEDTAVYYCGIPIGGTWNWGQGTQVTVSSGGGGSGGG GSEVHLVESGGGLVQAGGSLRLSCVASGSTFSGYGIVWHRQ RPGKQRELVAVISSDGTTNYGDSVRGRFTISRDNAKNTLYLQ MNSLEPEDTAVYYCGIPIGGTWNWGQGTQVTVSSEPKSADK THTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVA VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHE

[0495]

[0496] ALHNHYTQKSLSLSPG

[0497] In embodiments, a multivalent antibody including a sequence that is less than 100% identical to a sequence shown in one or more of Table 4 to Table 6 retains affinity for PD-1 that is substantially equivalent to a multivalent antibody including a sequence that is 100% identical to a sequence show n in one or more of Table 4 to Table 7.

[0498] In embodiments, a multivalent antibody including a sequence that is less than 100% identical to a sequence shown in one or more of Table 4 to Table 7 has less affinity for PD-1 than a multivalent antibody including a sequence that is 100% identical to a sequence shown in one or more of Table 4 to Table 7.

[0499] Illustrative Multivalents

[0500] In embodiments, the multivalent antibody includes a first antibody region including CDR- Hl, CDR-H2, and CDR-H3 sequences from a single row of Table 1, e g., SEQ ID NO: 1 to SEQ ID NO: 3, and includes a second antibody region including CDR-H1, CDR-H2, and CDR-H3 sequences from a single row of Table 4, e.g., SEQ ID NO: 625 to SEQ ID NO: 627. 062460-503001WG In embodiments, the multivalent antibody includes a third antibody region including CDR-Hl, CDR-H2, and CDR-H3 sequences from a single row of Table 1, e.g., SEQ ID NO: 1 to SEQ ID NO: 3, and / or includes a fourth antibody region including CDR-H1, CDR-H2, and CDR-H3 sequences from a single row of Table 4, e.g., SEQ ID NO: 625 to SEQ ID NO: 627.

[0501] In embodiments, the multivalent antibody includes a first antibody region including CDR-Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences from a single row of Table 1, e.g., SEQ ID NO: 1 to SEQ ID NO: 3, and includes a second antibody region including CDR-Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences from a single row of Table 5, e g, SEQ ID NO: 718 to SEQ ID NO: 723.

[0502] In embodiments, the multivalent antibody includes a third antibody region including CDR-Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences from a single row of Table 1, e.g., SEQ ID NO: 1 to SEQ ID NO: 6, and / or includes a fourth antibody region including CDR-Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences from a single row of Table 5. e g., SEQ ID NO: 718 to SEQ ID NO: 723.

[0503] In embodiments, the multivalent antibody includes a first antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in Table 2 or Table 3, e.g., SEQ ID NO: 469, and includes a second antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in Table 6 or Table 7, e.g., SEQ ID NO: 736.

[0504] In embodiments, the multivalent antibody includes a third antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in Table 2 or Table 3, e.g., SEQ ID NO: 469, and / or includes a fourth antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in Table 5, e.g., SEQ ID NO: 736.

[0505] In embodiments, the multivalent antibody includes a first antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 2. e.g., SEQ ID NO: 469. and one VL sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VL sequence shown in the single row of Table 2, e.g., SEQ ID NO: 470, and includes a second antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 6, e.g., SEQ ID NO: 736, and one VL sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VL sequence shown in the single row of Table 6, e.g., SEQ ID NO: 737.

[0506] In embodiments, the multivalent antibody includes a third antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence 062460-503001WG shown in a single row of Table 2. e.g., SEQ ID NO: 469. and one VL sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VL sequence shown in the single row of Table 2, e.g., SEQ ID NO: 470, and / or includes a fourth antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 6, e.g., SEQ ID NO: 736, and one VL sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VL sequence shown in the single row of Table 6, e.g., SEQ ID NO: 737.

[0507] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, and an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively.

[0508] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2. and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780, and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 781.

[0509] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780, and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 782.

[0510] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751 and an anti-CD2 antibody region that is at least 90% identical (e g., 95%, 99%, or 100% identical) to SEQ ID NO: 604..

[0511] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751. an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 062460-503001WG 780, and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 781.

[0512] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780, and a constant region that is at least 90% identical (e g., 95%, 99%, or 100% identical) to SEQ ID NO: 782.

[0513] For the multivalent antibody provided herein, in embodiments, the anti-PD-1 antibody region and the anti-CD2 antibody region are independently an scFv domain. A single chain antibody includes a variable light chain and a variable heavy chain, in contrast to an immunoglobulin antibody, which includes two identical pairs of polypeptide chains, each pair having one light chain and one heavy chain. The variable light chain and the variable heavy chain in a single chain antibody may be linked through a linker peptide. In embodiments, the anti-PD-1 antibody region includes an scFv domain. In embodiments, the anti-PD-1 antibody region is an scFv domain. In embodiments, the anti-CD2 antibody region includes an scFv domain. In embodiments, the anti-CD2 antibody region is an scFv domain. In embodiments, the anti-PD-1 antibody region includes a first single chain variable fragment (scFv) and the anti-CD2 antibody region includes a second scFv. In embodiments, the anti-PD-1 antibody region is a first single chain variable fragment (scFv) and the anti-CD2 antibody region is a second scFv.

[0514] For the multivalent antibody provided herein, in embodiments, the anti-PD-1 antibody region and the anti-CD2 antibody region are independently a Fab fragment. Thus, in embodiments the multivalent antibody may include an anti-PD-1 antibody region and an anti-CD2 antibody region each independently including a heavy chain (e.g., including a constant and a variable region) and a light chain (e.g., including a constant and a variable region). In embodiments, the Fab fragment includes a humanized heavy chain (e.g., including a constant and a variable region) and a humanized light chain (e.g., including a constant and a variable region). In embodiments, the anti-PD-1 antibody region includes a Fab fragment. In embodiments, the anti-PD-1 antibody region is a Fab fragment. In embodiments, the anti-CD2 antibody region includes a Fab fragment. In embodiments, the anti-CD2 antibody region is a Fab fragment. In embodiments, the anti-PD-1 antibody region includes a first Fab fragment and the anti-CD2 antibody region includes a second Fab fragment. In embodiments, the anti-PD-1 antibody region is a first a Fab fragment and the anti-CD2 antibody region is a second a Fab fragment.

[0515] For the multivalent antibody provided herein, in embodiments, the anti-PD-1 antibody region and the anti-CD2 antibody region are independently a Fab’ fragment. Thus, in 062460-503001WG embodiments, the anti-PD-1 antibody region includes a Fab' fragment. In embodiments, the anti-PD-1 antibody region is a Fab’ fragment. In embodiments, the anti-CD2 antibody region includes a Fab’ fragment. In embodiments, anti-CD2 antibody region is a Fab’ fragment. In embodiments, the anti-PD-1 antibody region includes a first Fab’ fragment and the anti-CD2 antibody region includes a second Fab' fragment. In embodiments, the anti-PD-1 antibody region includes a first Fab’ fragment. In embodiments, the anti-CD2 antibody region includes a second Fab’ fragment. In embodiments, the anti-PD-1 antibody region is a first Fab’ fragment. In embodiments, the anti-CD2 antibody region is a second Fab’ fragment. In embodiments, the first antibody region is a first Fab’ fragment and the second antibody region is a second Fab’ fragment.

[0516] In embodiments, the anti-PD-1 antibody region includes a variable domain of heavy chain (VHH). In embodiments, the anti-PD-1 antibody region is a variable domain of heavy chain (VHH). For the multivalent antibody provided herein, in embodiments, the anti-PD-1 antibody region includes a heavy chain variable domain (VH) or a variable domain of heavy chain (VHH). In embodiments, the anti-PD-1 antibody region does not include a variable light chain domain (VL). In embodiments, the anti-PD-1 antibody region does not include a constant region (e.g. CHI region).

[0517] In embodiments, the anti-PD-1 antibody region includes a peptibody. In embodiments, the anti-PD-1 antibody region is a peptibody.

[0518] In embodiments, the multivalent is a serially linked VHH. In some cases, the serially linked VHH comprises one anti-CD2 VHH (e.g., from Table 3), a linker (e.g., from Table 10), one anti-PD-1 VHH (e.g., from Table 4 or Table 7), a linker (e.g., from Table 10), and one anti-human serum albumin (HSA) VHH (e.g., from Table 11 or VHH sequences capable of binding to HSA that are known in the art. e g., ISOXTEND®). and an optional C-terminal extension (e.g., having a sequence of AAA). The present disclosure comprises over 12,300 possible combinations of serially linked VHH. Alternately, multivalents of this general format has the one anti-CD2 VHH, one anti-PD-1 VHH and one anti-human serum albumin (HSA) VHH in any order. The order of VHH is unlimited. In some cases a serially linked VHH comprises one VHH directed to CD2 and one to PD-1; a serially linked VHH comprises more than one VHH directed to CD2 and one to PD1; a serially linked VHH comprises one VHH directed to CD2 and more than one VHH to PD1; a serially linked VHH comprises more than one VHH directed to CD2 and more than one VHH to PD1; and / or a serially linked VHH comprises one or more VHH directed to an antigen that promotes stability and / or longevity of a serially linked VHH. In embodiments, the serially linked VHH lacks a constant domain, e.g., an Fc domain.

[0519] In embodiments, the scVhh-74 multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 062460-503001WG 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HS A antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 998 (GFTFSSFG), SEQ ID NO: 999 (ISGSGSDT). and SEQ ID NO: 1000 (TIGGGLSR) respectively.

[0520] In embodiments, the scVhh-94 multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 1001 (GFTFRSFG), SEQ ID NO: 1002 (ISGSGSDT), and SEQ ID NO: 1003 (TISGSLSR) respectively.

[0521] In embodiments, the scVhh-100 multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 1004 (GFTFRSFG), SEQ ID NO: 1005 (ISGSGSDT), and SEQ ID NO: 1006 (TIGGVLSR) respectively.

[0522] In embodiments, the scVhh-74 multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Cham CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 1007 (GFTFSSFG), SEQ ID NO: 1008 (ISGSGSDT). and SEQ ID NO: 1009 (GGGLSR) respectively.

[0523] In other embodiments, the serial linked VHH comprises a constant domain. See, FIG. 1H. The constant region may be at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780 and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 781 or 782. Another term for a serially linked VHH is a single chain VHH or scVHH.

[0524] In embodiments, the multivalent is a serially linked VHH having a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VHH sequences shown in Table 8. 062460-503001WG In embodiments, a multivalent antibody comprising a sequence that is less than 100% identical to a sequence shown in Table 8 comprises one, two or three amino acid mutations which are independently a substitution mutation, a deletion mutation, an insertion mutation, or a combination thereof.

[0525] Table 8 Serially linked VHHs

[0526] Name Sequence SEQ ID NO

[0527] scVhh-1 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 783

[0528] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCAASGRTISGLI NIAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKP EDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSAAAEVQLLESGGGLVQP GGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFT ISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSAAA

[0529] scVhh-2 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 784

[0530] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGW FRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDT AVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSAAAEVQLLESGGGLVQP GGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFT ISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSAAA

[0531] scVhh-3 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 785

[0532] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSAAAEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFG MSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRP EDTAVYYCTIGGSLSRSSQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCAAS GRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVY LQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSAAA

[0533] scVhh-4 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 786

[0534] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSAAAEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSW VRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDT AVYYCTIGGSLSRSSQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFT FSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQI NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSAAA

[0535] scVhh-5 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 787

[0536] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREF VAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAA GYYSGVVFTADYDYTYWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCAAS GRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVY LQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSAAA

[0537] scVhh-6 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 788

[0538] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSAAAEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRES VAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVF

[0539]

[0540] STVLTPVAEKFDLWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFT Name Sequence SEQ ID NO FSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQI NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSAAA

[0541] scVhh-7 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 789

[0542] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCAASGRTISGLI MAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKP EDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSAAAEVQLLESGGGLVQP GGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFT ISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGAAA

[0543] scVhh-7t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 790

[0544] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCAASGRTISGLI MAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKP EDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSAAAEVQLLESGGGLVQP GGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFT ISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG

[0545] scVhh-8 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 791

[0546] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGW FRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDT AVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSAAAEVQLLESGGGLVQP GGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFT ISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGAAA

[0547] scVhh-8t EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 792

[0548] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGW FRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDT AVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSAAAEVQLLESGGGLVQP GGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFT ISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[0549]

[0550] SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA Name Sequence SEQ ID NO VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG

[0551] scVhh-9 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 793

[0552] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSAAAEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFG MSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRP EDTAVYYCTIGGSLSRSSQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCAAS GRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVY LQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGAAA

[0553] scVhh-9t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 794

[0554] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSAAAEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFG MSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRP EDTAVYYCTIGGSLSRSSQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCAAS GRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVY LQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG

[0555] scVhh-10 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 795

[0556] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSAAAEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSW VRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDT AVYYCTIGGSLSRSSQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFT FSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQI NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGAAA

[0557] scVhh-lOt EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 796

[0558] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSAAAEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSW VRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDT AVYYCTIGGSLSRSSQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFT FSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQI NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[0559]

[0560] SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA Name Sequence SEQ ID NO VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG

[0561] scVhh-11 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 797

[0562] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREF VAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAA GYYSGVVFTADYDYTYWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCAAS GRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVY LQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGAAA

[0563] scVhh-llt EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 798

[0564] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREF VAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAA GYYSGVVFTADYDYTYWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCAAS GRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVY LQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG

[0565] scVhh-12 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 799

[0566] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSAAAEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRES VAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVF STVLTPVAEKFDLWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFT FSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQI NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGAAA

[0567] scVhh-12t EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 800

[0568] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSAAAEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRES VAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVF STVLTPVAEKFDLWGQGTLVTVSSAAAEVQLVESGGGLVQPGGSLRLSCVASGFT FSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQI NNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGSHHHHHH ENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[0569]

[0570] SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA Name Sequence SEQ ID NO VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG

[0571] scVhh-13 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 801

[0572] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCAASGRTISG LIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSL KPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSGGEVQLLESGGG LVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVK GRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSAAA

[0573] scVhh-14 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 802

[0574] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHM GWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPD DTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGSGGEVQLLESGGG LVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVK GRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSAAA

[0575] scVhh-15 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 803

[0576] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGSGGEVQLLESGGGLVQPGGSLRLSCAASGFTFRS FGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSL RPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLS CAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAK NTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSAAA

[0577] scVhh-16 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 804

[0578] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGSGGEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGM SWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPE DTAVYYCTIGGSLSRSSQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVA SGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTV YLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSAAA

[0579] scVhh-17 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 805

[0580] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKER EFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKS AAGYYSGWFTADYDYTYWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLS CAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAK NTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSAAA

[0581] scVhh-18 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 806

[0582] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVR ESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGET VFSTVLTPVAEKFDLWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVA SGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTV YLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSAAA

[0583] scVhh-19 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 807

[0584] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCAASGRTISG

[0585]

[0586] LIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSL Name Sequence SEQ ID NO KPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSGGEVQLLESGGG LVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVK GRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGAAA

[0587] scVhh-19t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 808

[0588] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCAASGRTISG LIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSL KPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSGGEVQLLESGGG LVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVK GRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPG

[0589] scVhh-20 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 809

[0590] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHM GWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPD DTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGSGGEVQLLESGGG LVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVK GRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGAAA

[0591] scVhh-20t EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 810

[0592] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHM GWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPD DTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGSGGEVQLLESGGG LVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVK GRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPG

[0593] scVhh-21 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 811

[0594] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGSGGEVQLLESGGGLVQPGGSLRLSCAASGFTFRS

[0595]

[0596] FGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSL Name Sequence SEQ ID NO RPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLS CAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAK NTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGAAA

[0597] scVhh-21t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 812

[0598] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGSGGEVQLLESGGGLVQPGGSLRLSCAASGFTFRS FGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSL RPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLS CAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAK NTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPG

[0599] scVhh-22 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 813

[0600] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGSGGEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGM SWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPE DTAVYYCTIGGSLSRSSQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVA SGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTV YLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGAAA

[0601] scVhh-22t EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 814

[0602] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGSGGEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGM SWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPE DTAVYYCTIGGSLSRSSQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVA SGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTV YLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPG

[0603] scVhh-23 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 815

[0604] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKER

[0605]

[0606] EFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKS Name Sequence SEQ ID NO AAGYYSGWFTADYDYTYWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLS CAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAK NTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGAAA

[0607] scVhh-23t EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 816

[0608] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKER EFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKS AAGYYSGWFTADYDYTYWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLS CAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAK NTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPG

[0609] scVhh-24 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 817

[0610] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVR ESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGET VFSTVLTPVAEKFDLWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVA SGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTV YLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGAAA

[0611] scVhh-24t EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 818

[0612] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVR ESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGET VFSTVLTPVAEKFDLWGQGTLVTVSSGGSGGEVQLVESGGGLVQPGGSLRLSCVA SGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTV YLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSGGSHH HHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPG

[0613] scVhh-25 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 819

[0614] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0615]

[0616] TISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSD TLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0617] scVhh-26 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 820

[0618] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCVASGFTFS SYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINN LRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSD TLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0619] scVhh-27 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 821

[0620] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLLESGGGLVQPGGSLRLSCAASGF TFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQ MNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQ PGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRF TISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVT VSSAAA

[0621] scVhh-28 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 822

[0622] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGGGSGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTFR SFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNS LRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGG SLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTIS RDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVT VSSAAA

[0623] scVhh-29 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 823

[0624] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYC AAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQ PGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRF TISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVT VSSAAA

[0625] scVhh-30 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 824

[0626] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTP GKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYC AGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGG SLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTIS RDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVT VSSAAA

[0627] scVhh-31 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 825

[0628] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0629]

[0630] TISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSD TLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGAAA

[0631] scVhh-31t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 826

[0632] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSD TLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPG

[0633] scVhh-32 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 827

[0634] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCVASGFTFS SYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINN LRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSD TLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGAAA

[0635] scVhh-32t EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 828

[0636] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCVASGFTFS SYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINN LRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSD TLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPG

[0637] scVhh-33 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 829

[0638] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLLESGGGLVQPGGSLRLSCAASGF

[0639]

[0640] TFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQ Name Sequence SEQ ID NO MNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQ PGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRF TISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGAAA

[0641] scVhh-33t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 830

[0642] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLLESGGGLVQPGGSLRLSCAASGF TFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQ MNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQ PGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRF TISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPG

[0643] scVhh-34 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 831

[0644] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGGGSGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTFR SFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNS LRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGG SLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTIS RDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGAAA

[0645] scVhh-34t EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 832

[0646] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGGGGSGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTFR SFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNS LRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGG SLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTIS RDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPG

[0647] scVhh-35 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 833

[0648] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP

[0649]

[0650] GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYC Name Sequence SEQ ID NO AAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQ PGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRF TISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGAAA

[0651] scVhh-35t EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 834

[0652] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAP GKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYC AAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQ PGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRF TISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPG

[0653] scVhh-36 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 835

[0654] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTP GKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYC AGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGG SLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTIS RDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGAAA

[0655] scVhh-36t EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 836

[0656] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTP GKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYC AGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGG SLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTIS RDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVT VSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPG

[0657] scVhh-37 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 837

[0658] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSL

[0659]

[0660] RLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRD Name Sequence SEQ ID NO NAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGS TSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQ APGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVY YCTIGGSLSRSSQGTLVTVSSAAA

[0661] scVhh-38 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 838

[0662] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLS CVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAK NTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGS TSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQ APGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVY YCTIGGSLSRSSQGTLVTVSSAAA

[0663] scVhh-39 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 839

[0664] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSL RLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRD NSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGSTSGSGKPGSGE GSTKGEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAA ISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTV LTPVAEKFDLWGQGTLVTVSSAAA

[0665] scVhh-40 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 840

[0666] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSLRLS CAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSK NTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGSTSGSGKPGSGEGST KGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPR SGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGV VFTADYDYTYWGQGTLVTVSSAAA

[0667] scVhh-41 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 841

[0668] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSY HMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLR PDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSGSTSGSGKPGSGE GSTKGEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAA ISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTV LTPVAEKFDLWGQGTLVTVSSAAA

[0669] scVhh-42 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 842

[0670] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCAASGRTISGL IMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLK PEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGSTSGSGKPGSGEGST KGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPR SGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGV VFTADYDYTYWGQGTLVTVSSAAA

[0671] scVhh-43 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 843

[0672] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSL

[0673]

[0674] RLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRD Name Sequence SEQ ID NO NAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGS TSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQ APGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVY YCTIGGSLSRSSQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAAA

[0675] scVhh-43t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 844

[0676] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSL RLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRD NAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGS TSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQ APGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVY YCTIGGSLSRSSQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0677] scVhh-44 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 845

[0678] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLS CVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAK NTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGS TSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQ APGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVY YCTIGGSLSRSSQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAAA

[0679] scVhh-44t EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 846

[0680] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLS CVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAK NTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVFTADYDYTYWGQGTLVTVSSGS TSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQ APGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVY YCTIGGSLSRSSQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0681] scVhh-45 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 847

[0682] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSL

[0683]

[0684] RLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRD Name Sequence SEQ ID NO NSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGSTSGSGKPGSGE GSTKGEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAA ISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTV LTPVAEKFDLWGQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVIVIHEALHNHYTQKSLSLSPGAAA

[0685] scVhh-45t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 848

[0686] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSL RLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRD NSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGSTSGSGKPGSGE GSTKGEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAA ISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTV LTPVAEKFDLWGQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0687] scVhh-46 EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 849

[0688] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSLRLS CAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSK NTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGSTSGSGKPGSGEGST KGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPR SGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGV VFTADYDYTYWGQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAAA

[0689] scVhh-46t EVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAAISYIG 850

[0690] SRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTVLTPVA EKFDLWGQGTLVTVSSGSTSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSLRLS CAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSK NTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGSTSGSGKPGSGEGST KGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPR SGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGV VFTADYDYTYWGQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0691] scVhh-47 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 851

[0692] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSY

[0693]

[0694] HMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLR Name Sequence SEQ ID NO PDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSGSTSGSGKPGSGE GSTKGEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAA ISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTV LTPVAEKFDLWGQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAAA

[0695] scVhh-47t EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 852

[0696] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSY HMGWFRQAPGKEREFVAAIPRSGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLR PDDTAVYYCAAKSAAGYYSGWFTADYDYTYWGQGTLVTVSSGSTSGSGKPGSGE GSTKGEVQLVESGGGLVQPGGSLRLSCAASGRTISGLIMAWFRQTPGKVRESVAA ISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAGETVFSTV LTPVAEKFDLWGQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0697] scVhh-48 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 853

[0698] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCAASGRTISGL IMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLK PEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGSTSGSGKPGSGEGST KGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPR SGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGV VFTADYDYTYWGQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAAA

[0699] scVhh-48t EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSG 854

[0700] SDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTL VTVSSGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGGSLRLSCAASGRTISGL IMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQMNSLK PEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGSTSGSGKPGSGEGST KGEVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPR SGSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGV VFTADYDYTYWGQGTLVTVSSGGSHHHHHHENLYFQGDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0701] scVhh-49 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 855

[0702] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0703]

[0704] TISSLIMAWFRQTPGKERESVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLAPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0705] scVhh-50 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 856

[0706] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0707] scVhh-51 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 857

[0708] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLAPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSASRSSQGTLVT VSSAAA

[0709] scVhh-52 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 858

[0710] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSASRSSQGTLVT VSSAAA

[0711] scVhh-53 QVKLEESGGGLVQAGGSLRVSCTASVSTFSINALGWYRQAPGKARELVAAIGSDG 859

[0712] TVYYTDSVKGRFTISRDNAKNTVSLQMSSLKPEDTAVYYCNAAGKRIGSDGSIWF AVASFGSWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGRT ISSLIMAWFRQTPGKERESVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQM NSLKPEDTAVYYCAGETVFSTVLAPVYEKFDLWGQGTLVTVSSGGGGSGGGSEVQ LVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTV SSAAA

[0713] scVhh-54 QVKLEESGGGLVQAGGSLRVSCTASVSTFSINALGWYRQAPGKARELVAAIGSDG 860

[0714] TVYYTDSVKGRFTISRDNAKNTVSLQMSSLKPEDTAVYYCNAAGKRIGSDGSIWF AVASFGSWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGRT ISSLIMAWFRQTPGKERESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQM NSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSEVQ LVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTV SSAAA

[0715] scVhh-55 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 861

[0716] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0717]

[0718] TISSLIMAWFRQTPGKERESVAAISYSGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLAPVYEKFDLWGQGTLVTVSSGGGGSGGGSQV KLEESGGGLVQAGGSLRVSCTASVSTFSINALGWYRQAPGKARELVAAIGSDGTV YYTDSVKGRFTISRDNAKNTVSLQMSSLKPEDTAVYYCNAAGKRIGSDGSIWFAV ASFGSWGQGTQVTVSSAAA

[0719] scVhh-56 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 862

[0720] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSQV KLEESGGGLVQAGGSLRVSCTASVSTFSINALGWYRQAPGKARELVAAIGSDGTV YYTDSVKGRFTISRDNAKNTVSLQMSSLKPEDTAVYYCNAAGKRIGSDGSIWFAV ASFGSWGQGTQVTVSSAAA

[0721] scVhh-57 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 863

[0722] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0723] scVhh-57t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 864

[0724] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSS

[0725] scVhh-58 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 865

[0726] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSAFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0727] scVhh-58t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 866

[0728] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSAFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSS

[0729] scVhh-59 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 867

[0730] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0731]

[0732] TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSGFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0733] scVhh-59t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 868

[0734] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSGFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSS

[0735] scVhh-60 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 869

[0736] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFEMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0737] scVhh-60t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 870

[0738] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFEMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSS

[0739] scVhh-61 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 871

[0740] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFKMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0741] scVhh-61t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 872

[0742] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFKMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSS

[0743] scVhh-62 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 873

[0744] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0745]

[0746] TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFLMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0747] scVhh-62t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 874

[0748] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFLMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSS

[0749] scVhh-63 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 875

[0750] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFVMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0751] scVhh-63t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 876

[0752] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFVMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSS

[0753] scVhh-64 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 877

[0754] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISASGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0755] scVhh-64t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 878

[0756] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISASGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSS

[0757] scVhh-65 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 879

[0758] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0759]

[0760] TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISSSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSSAAA

[0761] scVhh-65t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 880

[0762] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISSSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVT VSS

[0763] scVhh-66 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 881

[0764] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTSGGSLSRSSQGTLVT VSSAAA

[0765] scVhh-66t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 882

[0766] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTSGGSLSRSSQGTLVT VSS

[0767] scVhh-67 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 883

[0768] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTTGGSLSRSSQGTLVT VSSAAA

[0769] scVhh-67t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 884

[0770] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTTGGSLSRSSQGTLVT VSS

[0771] scVhh-68 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 885

[0772] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0773]

[0774] TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIEGSLSRSSQGTLVT VSSAAA

[0775] scVhh-68t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 886

[0776] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIEGSLSRSSQGTLVT VSS

[0777] scVhh-69 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 887

[0778] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIFGSLSRSSQGTLVT VSSAAA

[0779] scVhh-69t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 888

[0780] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIFGSLSRSSQGTLVT VSS

[0781] scVhh-70 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 889

[0782] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIKGSLSRSSQGTLVT VSSAAA

[0783] scVhh-70t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 890

[0784] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIKGSLSRSSQGTLVT VSS

[0785] scVhh-71 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 891

[0786] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0787]

[0788] TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTILGSLSRSSQGTLVT VSSAAA

[0789] scVhh-71t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 892

[0790] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTILGSLSRSSQGTLVT VSS

[0791] scVhh-72 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 893

[0792] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGALSRSSQGTLVT VSSAAA

[0793] scVhh-72t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 894

[0794] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGALSRSSQGTLVT VSS

[0795] scVhh-73 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 895

[0796] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGELSRSSQGTLVT VSSAAA

[0797] scVhh-73t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 896

[0798] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGELSRSSQGTLVT VSS

[0799] scVhh-74 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 897

[0800] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0801]

[0802] TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGGLSRSSQGTLVT VSSAAA

[0803] scVhh-74t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 898

[0804] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGGLSRSSQGTLVT VSS

[0805] scVhh-75 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 899

[0806] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGRLSRSSQGTLVT VSSAAA

[0807] scVhh-75t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 900

[0808] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGRLSRSSQGTLVT VSS

[0809] scVhh-76 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 901

[0810] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLARSSQGTLVT VSSAAA

[0811] scVhh-76t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 902

[0812] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLARSSQGTLVT VSS

[0813] scVhh-77 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 903

[0814] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0815]

[0816] TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLGRSSQGTLVT VSSAAA

[0817] scVhh-77t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 904

[0818] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLGRSSQGTLVT VSS

[0819] scVhh-78 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 905

[0820] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRASQGTLVT VSSAAA

[0821] scVhh-78t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 906

[0822] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRASQGTLVT VSS

[0823] scVhh-79 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 907

[0824] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSGFGMSWVRQAPGKGLEWVSSISSSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGGLSRSSQGTLVT VSSAAA

[0825] scVhh-79t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 908

[0826] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSGFGMSWVRQAPGKGLEWVSSISSSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGGLSRSSQGTLVT VSS

[0827] scVhh-80 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 909

[0828] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR

[0829]

[0830] TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSGFGMSWVRQAPGKGLEWVSSISSSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTSGGGLSRSSQGTLVT VSSAAA

[0831] scVhh-80t EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRSG 910

[0832] SNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGR TISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLVESGGGLVQPGNSLRLSCAASGFTFSGFGMSWVRQAPGKGLEWVSSISSSGSD TLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTSGGGLSRSSQGTLVT VSS

[0833] scVhh-81 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 911

[0834] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISGLIMAWFRQTPGKVRESVAAISYIGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVAEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTV SSAAA

[0835] scVhh-82 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 912

[0836] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTV SSAAA

[0837] scVhh-83 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 913

[0838] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYIYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIVGSLSRSSQGTLVTV SSAAA

[0839] scVhh-84 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 914

[0840] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTISGGLSRSSQGTLVTV SSAAA

[0841] scVhh-85 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 915

[0842] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF

[0843]

[0844] TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS Name Sequence SEQ ID NO GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGLLSRSSQGTLVTV SSAAA

[0845] scVhh-86 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 916

[0846] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTILGSLSRSSQGTLVTV SSAAA

[0847] scVhh-87 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 917

[0848] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS ETLYAESVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTV SSAAA

[0849] scVhh-88 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 918

[0850] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTITGSLSRSSQGTLVTV SSAAA

[0851] scVhh-89 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 919

[0852] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFSMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTV SSAAA

[0853] scVhh-90 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 920

[0854] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYIYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIRGSLSRSSQGTLVTV

[0855]

[0856] SSAAA Name Sequence SEQ ID NO

[0857] scVhh-91 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 921

[0858] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGVVF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGFLSRSSQGTLVTV SSAAA

[0859] scVhh-92 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 922

[0860] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFTMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTV SSAAA

[0861] scVhh-93 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 923

[0862] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFHMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTV SSAAA

[0863] scVhh-94 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 924

[0864] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTISGSLSRSSQGTLVTV SSAAA

[0865] scVhh-95 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 925

[0866] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFAMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTV SSAAA

[0867] scVhh-96 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 926

[0868] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV

[0869]

[0870] QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS Name Sequence SEQ ID NO DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGILSRSSQGTLVTV SSAAA

[0871] scVhh-97 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 927

[0872] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIQGSLSRSSQGTLVTV SSAAA

[0873] scVhh-98 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 928

[0874] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGQLSRSSQGTLVTV SSAAA

[0875] scVhh-99 EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 929

[0876] GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGKLSRSSQGTLVTV SSAAA

[0877] scVhh- EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 930 100 GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGVLSRSSQGTLVTV SSAAA

[0878] scVhh- EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 931 101 GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGELSRSSQGTLVTV SSAAA

[0879] scVhh- EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 932 102 GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF

[0880] TADYDYIYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS

[0881]

[0882] GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ 062460-503001WG Name Sequence SEQ ID NO MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFIMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTV SSAAA

[0883] scVhh- EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 933 103 GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGGLSRSSQGTLVTV SSAAA

[0884] scVhh- EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 934 104 GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIAGSLSRSSQGTLVTV SSAAA

[0885] scVhh- EVQLVESGGGLVQPGGSLRLSCVASGFTFSSYHMGWFRQAPGKEREFVAAIPRS 935 105 GSNIGYSAFVKDRGTISRDNAKNTVYLQINNLRPDDTAVYYCAAKSAAGYYSGWF TADYDYTYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAAS GRTISSLIMAWFRQTPGKERESVAAISYEGSRTYYEESVKGRFTISRDNAKNTVYLQ MNSLKPEDTAVYYCAGETVFSTVLTPVYEKFDLWGQGTLVTVSSGGGGSGGGSEV QLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGS DTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIIGSLSRSSQGTLVTVS

[0886]

[0887] SAAA

[0888] In Table 8, the named multivalent antibodies including the letter “t” after the number are truncated versions of the multivalent antibodies. These truncated multivalent antibodies lack the C-terminal alanine triplet (AAA) which is present in the multivalent antibodies lacking the letter “t”. In various embodiments, a multivalent antibody of the present disclosure may include the C-terminal alanine triplet or may lack the C-terminal alanine triplet. The C-terminal alanine triplet may help prevent Anti-Drug Antibody (ADA) response (pre-existing ADA), which may affect the function and PK of the multivalent antibodies when used. The AAA may occlude and / or mask an epitope in VHHs that is known to be immunogenic. The terminal AAA may be omitted from a sequence if the multivalent comprise a C-terminal constant region, e.g.,. See FIG. 1H. FIG. 1H shows that a serial linked VHH has an AAA or a constant region (exemplified there as His-TEV-Fc); however, a serial linked VHH can have both an AAA and a constant region. Any of the herein disclosed multivalent antibodies may further comprise a constant region that is at least 90% 062460-503001WG identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780 and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 781 or 782.

[0889] In embodiments, the multivalent antibody includes a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 897.

[0890] In embodiments, the multivalent antibody includes a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 924.

[0891] In embodiments, the multivalent antibody includes a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 930.

[0892] For the multivalent antibody provided herein, in embodiments, the anti-PD-1 antibody region and the anti-CD2 antibody region are attached by a linker. In embodiments, the linker is a polypeptide linker. In embodiments, the polypeptide linker includes repeats of serine and glycine for flexibility and / or solubility. In one example, an anti-PD-1 antibody region may be attached to an anti-CD2 antibody region by a polypeptide linker, wherein the anti-PD-1 antibody region is a first scFv and the anti-CD2 antibody region is a second scFv. In another example, an anti-PD-1 antibody region may be attached to an anti-CD2 antibody region by a polypeptide linker, wherein the anti-PD-1 antibody region is a VHH and the anti-CD2 antibody region is a Fab fragment. For the multivalent antibody provided herein, including embodiments thereof, the anti-CD2 antibody region and the anti-PD-1 antibody region may be any combination of antibody fragments or variants thereof as described herein attached by a polypeptide linker. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 10 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 15 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 20 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 25 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 30 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 35 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 40 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 45 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 50 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 55 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 60 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 65 amino acid residues to about 150 amino acid residues in 062460-503001WG length. In embodiments, the polypeptide linker is from about 70 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 75 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 80 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 85 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 90 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 95 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 100 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 105 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 110 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 115 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 120 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 125 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 130 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 135 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 140 amino acid residues to about 150 amino acid residues in length. In embodiments, the polypeptide linker is from about 145 amino acid residues to about 150 amino acid residues in length.

[0893] In embodiments, the polypeptide linker is from about 5 amino acid residues to about 145 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 140 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 135 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 130 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 125 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 120 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 115 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 110 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 105 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 100 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 95 amino acid residues in length. In embodiments, the polypeptide 062460-503001WG linker is from about 5 amino acid residues to about 90 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 85 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 80 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 75 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 70 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 65 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 60 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 55 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 50 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 45 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 40 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 35 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 30 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 25 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 20 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 15 amino acid residues in length. In embodiments, the polypeptide linker is from about 5 amino acid residues to about 10 amino acid residues in length. In embodiments, the polypeptide linker is about 5 amino acid residues, 10 amino acid residues, 15 amino acid residues, 20 amino acid residues, 25 amino acid residues. 30 amino acid residues, 35 amino acid residues, 40 amino acid residues, 45 amino acid residues, 50 amino acid residues, 55 amino acid residues, 60 amino acid residues, 65 amino acid residues, 70 amino acid residues, 75 amino acid residues, 80 amino acid residues, 85 amino acid residues, 90 amino acid residues, 95 amino acid residues, 100 amino acid residues, 105 amino acid residues, 110 amino acid residues, 115 amino acid residues, 120 amino acid residues, 125 amino acid residues, 130 amino acid residues, 135 amino acid residues, 140 amino acid residues, 145 amino acid residues, or 150 amino acid residues in length.

[0894] For the multivalent antibody provided herein, in embodiments, the anti-PD-1 antibody region and the anti-CD2 antibody region are attached by a first Fc portion and a second Fc portion, wherein the first Fc portion and the second Fc portion dimerize to form an Fc region, thereby attaching the anti-PD-1 antibody region and the anti-CD2 antibody region. Thus, in embodiments, the anti-PD-1 antibody region includes a first Fc portion and the anti-CD2 antibody region includes 062460-503001WG a second Fc portion. An " Fc portion” as referred to herein is a polypeptide including an antibody CH2 domain or fragment thereof attached (covalently and / or non-covalently) to an antibody CH3 domain or fragment thereof. Upon binding of two Fc portions, an antibody Fc region is formed. Thus, an Fc region may include a first Fc portion non-covalently or covalently bound to a second Fc portion. In embodiments, the CH3 domain of the first Fc portion is non-covalently bound to the CH3 domain of the second Fc portion. In embodiments, the CH2 domain of the first Fc portion is covalently bound to the CH2 domain of the second Fc portion. In embodiments, the CH2 domain of the first Fc portion is bound to the CH2 domain of the second Fc portion through a disulfide linkage. In embodiments, the Fc portion includes a CH2 domain and a CH3 domain. In embodiments, the Fc portion includes from the N-terminus to the C-terminus a CH2 domain and a CH3 domain. Thus, in embodiments, the first Fc portion and the second Fc portion are attached, thereby forming an Fc region.

[0895] In embodiments, the multivalent antibody includes a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a sequence shown in Table 9.

[0896] Some of the Fc regions comprise “knob"’ or “hole” motifs. In some cases, the Fc region lacks “knob” and “hole” motifs.

[0897] Table 9 Constant Regions

[0898] Name Sequence SEQ ID NO LALAPG- ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP 773 KiH K AVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALGA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG LALAPG GGSGGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH 774 KiH K EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYK

[0899] VHH CKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPG LALAPG- ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP 775 KiH H AVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALGA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNR FTQKSLSLSPG LALAPG- GGSGGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH 776 KiH H EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYK

[0900] VHH CKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS

[0901]

[0902] VMHEALHNRFTQKSLSLSPG 062460-503001WG Name Sequence SEQ ID NO FEA FE- ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP 777

[0903] FcT AVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG FEA FE- EPKSADKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWAVSHE 778

[0904] FcT-VHH DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPG

[0905] C kappa RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQ 779

[0906] ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0907] Knob- GSGGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCWVDVSHE 780 LALAPG- DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYK

[0908] YTE CKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPG

[0909] Hole-RF- GGSGGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVWDVSH 781 LALAPG- EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYK

[0910] YTE CKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS VMHEALHNRFTQKSLSLSPG

[0911] Hole- GGSGGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCWVDVSH 782 LALAPG- EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYK

[0912] YTE CKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS

[0913]

[0914] VMHEALHNHYTQKSLSLSPG

[0915] In Table 9, " LALAPG’7refers to a set of three mutations: (1) L - A, (2) L -> A, and (3) P - G. In Table 9, the term “FE”

[0916] SEQ ID 779 is a light chain (kappa) sequence, not a heavy chain (Fc-containing) sequence; however, for simplicity, in this disclosure, we are referring to it as an Fc sequence.

[0917] Table 10 Linker Sequences

[0918] Name Sequence SEQ ID NO

[0919] A3 AAA 936

[0920] GS5 GGSGG 937

[0921] GS9 GGGGSGGGS 938

[0922]

[0923] W218 GSTSGSGKPGSGEGSTKG 939 Table 11 HSA VHH Sequences

[0924] Name Sequence SEQ ID NO

[0925] aHSAl_l EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 940

[0926] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[0927] aHSAl_2 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 941

[0928] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[0929] aHSAl_3 EVQLVESGGGLVQPGNSLRLSCAASGFTFSAFGMSWVRQAPGKGLEWVSS 942

[0930] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[0931] aHSAl_4 EVQLVESGGGLVQPGNSLRLSCAASGFTFSGFGMSWVRQAPGKGLEWVS 943

[0932] SISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSL S RSSQGTLVTVSS

[0933] aHSAl_5 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFEMSWVRQAPGKGLEWVSS 944

[0934] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[0935] aHSAl_6 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFKMSWVRQAPGKGLEWVSS 945

[0936] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[0937] aHSAl_7 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFLMSWVRQAPGKGLEWVSSI 946

[0938] SGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSR SSQGTLVTVSS

[0939] aHSAl_8 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFVMSWVRQAPGKGLEWVSS 947

[0940] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[0941] aHSAl_9 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 948

[0942] ISASGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSR SSQGTLVTVSS

[0943] aHSAl_10 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 949

[0944] ISSSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSR SSQGTLVTVSS

[0945] aHSAl_ll EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 950

[0946] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTSGGSLS RSSQGTLVTVSS

[0947] aHSAl_12 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 951

[0948] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTTGGSLS RSSQGTLVTVSS

[0949] aHSAl_13 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 952

[0950] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIEGSLSR SSQGTLVTVSS

[0951] aHSAl_14 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 953

[0952] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIFGSLSR

[0953]

[0954] SSQGTLVTVSS Name Sequence SEQ ID NO

[0955] aHSAl_15 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 954

[0956] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIKGSLSR SSQGTLVTVSS

[0957] aHSAl_16 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 955

[0958] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTILGSLSR SSQGTLVTVSS

[0959] aHSAl_17 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 956

[0960] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGALS RSSQGTLVTVSS

[0961] aHSAl_18 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 957

[0962] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGELS RSSQGTLVTVSS

[0963] aHSAl_19 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 958

[0964] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGGLS RSSQGTLVTVSS

[0965] aHSAl_20 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 959

[0966] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGRLS RSSQGTLVTVSS

[0967] aHSAl_21 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 960

[0968] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLA RSSQGTLVTVSS

[0969] aHSAl_22 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 961

[0970] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLG RSSQGTLVTVSS

[0971] aHSAl_23 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS 962

[0972] ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLS RASQGTLVTVSS

[0973] aHSAl_24 EVQLVESGGGLVQPGNSLRLSCAASGFTFSGFGMSWVRQAPGKGLEWVS 963

[0974] SISSSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGGL S RSSQGTLVTVSS

[0975] aHSAl_25 EVQLVESGGGLVQPGNSLRLSCAASGFTFSGFGMSWVRQAPGKGLEWVS 964

[0976] SISSSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTSGGGL S RSSQGTLVTVSS

[0977] aHSA2 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 965

[0978] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[0979] aHSA2_32 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 966

[0980] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIVGSLS RSSQGTLVTVSS

[0981] aHSA2_39 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 967

[0982] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTISGGLS RSSQGTLVTVSS

[0983] aHSA2_36 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 968

[0984] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGLLS

[0985]

[0986] RSSQGTLVTVSS Name Sequence SEQ ID NO

[0987] aHSA2_16 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 969

[0988] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTILGSLS RSSQGTLVTVSS

[0989] aHSA2_40 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 970

[0990] ISGSGSETLYAESVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[0991] aHSA2_31 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 971

[0992] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTITGSLS RSSQGTLVTVSS

[0993] aHSA2_44 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFSMSWVRQAPGKGPEWVSS 972

[0994] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[0995] aHSA2_29 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 973

[0996] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIRGSLS RSSQGTLVTVSS

[0997] aHSA2_33 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 974

[0998] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGFLS RSSQGTLVTVSS

[0999] aHSA2_45 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFTMSWVRQAPGKGPEWVSSI 975

[1000] SGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSR SSQGTLVTVSS

[1001] aHSA2_42 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFHMSWVRQAPGKGPEWVSS 976

[1002] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[1003] aHSA2_30 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 977

[1004] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTISGSLS RSSQGTLVTVSS

[1005] aHSA2_41 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFAMSWVRQAPGKGPEWVSS 978

[1006] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS

[1007] aHSA2_34 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 979

[1008] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGILSR SSQGTLVTVSS

[1009] aHSA2_28 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 980

[1010] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIQGSLS RSSQGTLVTVSS

[1011] aHSA2_37 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 981

[1012] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGQLS RSSQGTLVTVSS

[1013] aHSA2_35 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 982

[1014] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGKLS RSSQGTLVTVSS

[1015] aHSA2_38 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 983

[1016] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGVLS

[1017]

[1018] RSSQGTLVTVSS 062460-503001WG Name Sequence SEQ

[1019] ID NO

[1020] aHSA2_18 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 984

[1021] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGELS RSSQGTLVTVSS

[1022] aHSA2_43 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFIMSWVRQAPGKGPEWVSSI 985

[1023] SGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSR SSQGTLVTVSS

[1024] aHSA2_19 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 986

[1025] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGGLS RSSQGTLVTVSS

[1026] aHSA2_26 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 987

[1027] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIAGSLS RSSQGTLVTVSS

[1028] aHSA2_27 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSS 988

[1029] ISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIIGSLSR

[1030]

[1031] SSQGTLVTVSS

[1032] An illustrative VHH capable of binding HSA is shown in Table 11 and comprises a sequence at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 940. In some cases, the wild type anti-HSA VHH has the sequence of SEQ ID NO: 940. Illustrative detuned anti-HSA VHH domains having reduced capacity for binding HSA due to one or more mutations relative to a wild type anti-HSA VHH, are shown in Table 11 and comprises a sequence at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 941 to 988, e.g., 958, 977, and 983.

[1033] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Cham CDRs (CDR-HL CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 958.

[1034] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2. and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region that is at least 90% identical (e.g.. 95%, 99%, or 100% identical) to SEQ ID NO: 977.

[1035] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising 062460-503001WG three Heavy Chain CDRs (CDR-H1. CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 983.

[1036] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 781, and an anti HSA antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 958.

[1037] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 781, and an anti HSA antibody region that is at least 90% identical (e.g.. 95%, 99%, or 100% identical) to SEQ ID NO: 977.

[1038] In embodiments, the multivalent antibody includes an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g.. 95%. 99%. or 100% identical) to SEQ ID NO: 781, and an anti HSA antibody region that is at least 90% identical (e g., 95%, 99%, or 100% identical) to SEQ ID NO: 983.

[1039] In embodiments, the anti-PD-1 antibody region is N-terminal to one or both of the anti-CD2 antibody region and / or the anti-HSA antibody region; the anti-CD2 antibody region is N-terminal to one or both of the anti- PD-1 antibody region and / or the anti-HSA antibody region; or the anti-HSA antibody region is N-terminal to one or both of the anti- PD-1 antibody region and / or the anti-CD2 antibody region. In some cases, the multivalent antibody has a configuration, progressing N-terminal to C-terminal, of PD1: CD2: HSA; PD1: HSA: CD2; CD2: PD1: HSA; HSA: PD1: CD2; HSA: CD2: PD1; or CD2: HSA: PD1.

[1040] In embodiments, a herein disclosed VHH, plurality of CDRs (i.e., three heavy chain CDRs or three heavy chain CDRs with three light CDRs), VL, VH, Fab, scFV, or a combination thereof may be used as a monospecific antibody, i.e., the antibody only binds to one antigen. For example, the VHH. plurality of CDRs (i.e., three heavy chain CDRs or three heavy chain CDRs with three light CDRs), VL, VH, Fab, scFV, or a combination thereof that are directed to CD2 may be included in a monospecific antibody. In embodiments, the monospecific antibody includes an antibody region including one or more Variable Heavy (VH) sequences that are at least 90% 062460-503001WG identical (e.g., 95%, 99%, or 100% identical) to the VH sequences shown in Table 2. In embodiments, the monospecific antibody includes an antibody region including one or more Variable Light (VL) sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VL sequences shown in Table 2. In embodiments, the monospecific antibody includes an antibody region including one or more VH sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VH sequences shown in Table 2 and one or more VL sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VL sequences shown in Table 2. In embodiments, the monospecific antibody includes an antibody region including a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 2. e.g., SEQ ID NO: 469. and one VL sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VL sequence shown in the single row of Table 2, e.g., SEQ ID NO: 470.

[1041] Any of the herein disclosed multivalent antibodies may further comprise a constant region that is at least 90% identical (e.g.. 95%. 99%, or 100% identical) to SEQ ID NO: 780 and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 781 or 782.

[1042] In an additional aspect, the present disclosure provides a polynucleotide or plurality of polynucleotides encoding a herein-disclosed multivalent antibody.

[1043] In yet an additional aspect, the present disclosure provides a vector comprising the polynucleotide or plurality of a herein-disclosed polynucleotides.

[1044] Table 12 Additional Sequences

[1045] Sequence SEQ ID NO

[1046]

[1047] GGSHHHHHHENLYFQG 989

[1048] Pharmaceutical Compositions

[1049] In an aspect, the present disclosure provides a pharmaceutical composition comprising a herein-disclosed multivalent antibody or monospecific antibody and a pharmaceutically acceptable carrier, diluent, or excipient. The multivalent antibody or monospecific antibody provided herein may be provided in a pharmaceutical composition suitable for administration to a subject.

[1050] In various aspects, the pharmaceutical composition is for use as a medicament in the treatment of an autoimmune disease or inflammatory disease or a graft-versus-host disease (GVHD). In embodiments, an effector cell is characterized by expression or overexpression of PD-1 and / or CD2. 062460-503001WG The pharmaceutical composition may include a combination of a multivalent antibody or monospecific antibody of the present disclosure and an agonist anti-PD-1 antibody. Non-limiting examples of anti-PD-1 agonist antibodies include rosnilimab and peresolimab.

[1051] The pharmaceutical composition may include a combination of a multivalent antibody or monospecific antibody of the present disclosure and an immunomodulatory drug. Non-limiting examples of immunomodulatory drugs include checkpoint inhibitors, adoptive T cell therapy, monoclonal antibody therapy, corticosteroids, tumor necrosis factor inhibitors, interleukin-1 (IL-1) inhibitors, interleukin-6 (IL-6) inhibitors, T cell inhibitors, B-cell inhibitors and Janus Kinase inhibitors. Additionally, the multivalent antibody may be combined with an immunosuppressant drug.

[1052] The pharmaceutical composition may include a combination of a multivalent antibody or monospecific antibody of the present disclosure and the standard of care, e.g., for treating an autoimmune disease or inflammatory disease or a graft-versus-host disease (GVHD).

[1053] Methods

[1054] Another aspect of the present disclosure is a method for dampening T cell signaling for the treatment of autoimmune diseases or inflammatory disease or in a graft-versus-host disease (GVHD).

[1055] In embodiments, the method comprises contacting an effector cell, e.g., a T cell, with an effective amount of a herein-disclosed multivalent antibody or monospecific antibody of the present disclosure. The method may be in vitro, ex vivo, or in vivo.

[1056] A further aspect of the present disclosure is a method of treating or preventing an autoimmune disease or inflammatory disease or suppresses graft-versus-host disease (GVHD) in a subject in need thereof, the method comprising contacting an effector cell (e.g., a T cell) with an effective amount of a herein-disclosed multivalent antibody or monospecific antibody. In embodiments, the effector cell, e.g.. T cell, is characterized by expression or overexpression of PD-1 and / or CD2.

[1057] The multivalent antibodies provided herein are contemplated to be effective for treating diseases (e.g. autoimmune disease or inflammatory disease or GVHD). As described throughout the specification, including in the Examples and Figures, the multivalent antibodies provided herein demonstrate superior dampening of T cell signaling, for example, compared to mono-specific PD-1 or CD2 antibodies and other multivalent antibody constructs. In an aspect is provided a method of treating or preventing an autoimmune disease or inflammatory disease or suppressing graft-versus-host disease (GVHD) in a subject in need thereof the method including, administering a therapeutically effective amount of the multivalent antibody provided herein including embodiments thereof to the subject. 062460-503001WG A therapeutically effective amount refers to an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend on the condition being treated. When administered in methods to treat a disease, the pharmaceutical compositions described herein will contain an amount of multivalent antibody effective to achieve the desired result, e.g., modulating the activity of a target molecule (e.g., PD-1 or CD2), and / or reducing, eliminating, or slowing the progression of disease symptoms. Determination of a therapeutically effective amount of a multivalent antibody or monospecific antibody provided herein is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[1058] In embodiments, the autoimmune diseases or inflammatory disease is Type 1 diabetes (T1D), Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE). Myasthenia gravis (MG), Autoimmune uveitis (AU), Sjogren's syndrome (SjS), Inflammatory bowel diseases (IBD), or Autoimmune hepatitis (AIH), Behcet's disease (BD).

[1059] In embodiments, the method includes administering to the subject a combination therapy including a multivalent antibody provided herein, with an agonist anti-PD-1 antibody. The combination of a multivalent antibody provided herein with an agonist anti-PD-1 antibody provides potent activity in suppressing T cell activation. In embodiments, the combination therapy (e.g. combination of a multivalent antibody provided herein including embodiments thereof with an agonist anti-PD-1 antibody) suppresses T cell suppression compared to T cell suppression by treatment with the anti-PD-1 antibody alone or the multivalent antibody alone. In embodiments, T cell suppression is measured by one or more markers of T cell suppression. In embodiments, T cell suppression is measured by a cytometric method. In embodiments, T cell suppression is measured by detection of CD8+ T cells. In embodiments, T cell suppression is measured by IL-2 expression or IFN-gamma expression.

[1060] In embodiments, the combination therapy including a multivalent antibody provided herein including embodiments thereof with an anti-PD-1 agonist antibody results in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6. 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6. 4.7, 4.8. 4.9, 5.0, 5.1. 5.2, 5.3, 5.4. 5.5, 5.6, 5.7, 5.8. 5.9, 6.0, 6.1. 6.2, 6.3, 6.4. 6.5, 6.6, 6.7, 6.8. 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63. 64. 65. 66. 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% greater T cell suppression compared to T cell suppression from treatment with a monotherapy including the multivalent antibody or an anti-PD-1 antibody alone. 062460-503001WG In embodiments, the combination therapy including a multivalent antibody provided herein including embodiments thereof with an anti-PD-1 antibody results in about 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, or 5-fold greater T cell suppression compared to T cell suppression from treatment with a monotherapy including the multivalent antibody or an anti-PD-1 antibody alone.

[1061] In embodiments, the method provided herein includes administering to the subject a therapeutically effective amount of a multivalent antibody and an anti-PD-1 antibody, as described above, wherein the combination has synergistic effect. In embodiments, the synergistic effect is more than a sum of effects from individual administration of the multivalent antibody or an anti-PD-1 antibody.

[1062] In embodiments, synergy between the multivalent antibody and an anti-PD-1 antibody may result in 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1. 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1. 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1. 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31. 32. 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57. 58. 59. 60. 61. 62. 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% greater T cell suppression than the sum of T cell suppression when the multivalent antibody or an anti-PD-1 antibody are used individually and separately.

[1063] For the method provided herein, in embodiments, the effective amount of a multivalent antibody and an anti-PD-1 antibody are a combined additive amount. In embodiments, the effective amount of a multivalent antibody and an anti-PD-1 antibody are a combined synergistic amount. In embodiments, the multivalent antibody and an anti-PD-1 antibody are administered sequentially or simultaneously.

[1064] A “synergistic amount” as used herein refers to the sum of a first amount (e.g., a multivalent antibody) and a second amount (e.g., an anti-PD-1 antibody) that results in a synergistic effect (i.e. an effect greater than an additive effect). Therefore, the terms "synergy", "synergism", "synergistic", "combined synergistic amount", and "synergistic therapeutic effect" which are used herein interchangeably, refer to a measured effect of the compound administered in combination where the measured effect is greater than the sum of the individual effects of each of the compounds provided herein administered alone as a single agent. More specifically, a “combined synergistic amount” is a combined amount of a first agent (e.g. a multivalent antibody) and second 062460-503001WG agent (e.g. an anti-PD-1 antibody) effective to provide a synergistic effect (e.g. for treating an autoimmune disease or inflammatory disease or a graft-versus-host disease (GVHD)). In embodiments, the methods herein including administering multivalent antibody and an anti-PD-1 antibody, include administering a combined sy nergistic amount of the multivalent antibody and an anti-PD-1 antibody. In embodiments, the pharmaceutical compositions herein including a multivalent antibody and an anti-PD-1 antibody, include a combined synergistic amount of the multivalent antibody and an anti-PD-1 antibody.

[1065] In embodiments, a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1. 2.2, 2.3, 2.4, 2.5. 2.6, 2.7, 2.8, 2.9, 3.0, 3.1. 3.2, 3.3, 3.4, 3.5. 3.6, 3.7, 3.8, 3.9. 4.0, 4.1, 4.2, 4.3. 4.4, 4.5, 4.6, 4.7. 4.8, 4.9, 5.0. 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41. 42. 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57.

[1066] 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the multivalent antibody provided herein when used separately from the an anti-PD-1 antibody.

[1067] Definitions

[1068] Prior to setting forth this disclosure in more detail, it may be helpful to an understanding thereof to provide definitions of certain terms to be used herein.

[1069] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of particular embodiments, preferred embodiments of compositions, methods and materials are described herein. For the purposes of the present disclosure, the following terms are defined below. Additional definitions are set forth throughout this disclosure.

[1070] The articles “a,” "an." and “the” are used herein to refer to one or to more than one (i.e., to at least one, or to one or more) of the grammatical obj ect of the article. By way of example, “an element” means one element or one or more elements.

[1071] The use of the alternative (e.g., “or”) should be understood to mean either one, both, or any combination thereof of the alternatives.

[1072] The term “and / or” should be understood to mean either one, or both of the alternatives. 062460-503001WG Throughout this specification, unless the context requires otherwise, the words “comprise”, “comprises” and “comprising” will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. By “consisting of’ is meant including, and limited to, whatever follows the phrase “consisting of.” Thus, the phrase “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present. By “consisting essentially of’ is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of’ indicates that the listed elements are required or mandatory, but that no other elements are present that materially affect the activity or action of the listed elements.

[1073] Reference throughout this specification to “one embodiment,” “an embodiment,” “a particular embodiment,” “a related embodiment,” “a certain embodiment,” “an additional embodiment,” or “a further embodiment” or combinations thereof means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. It is also understood that the positive recitation of a feature in one embodiment, serves as a basis for excluding the feature in a particular embodiment.

[1074] As used herein, the term “about” or “approximately” refers to a quantity', level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length. In one embodiment, the term “about” or “approximately” refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% about a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[1075] In the present description, any value range, e.g., concentration range, percentage range, or ratio range, or integer range and the like, is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. The term “about”, when immediately- preceding a number or numeral, means that the number or numeral ranges plus or minus 10%.

[1076] The term “increased” or “enhanced” amount of a physiological response, e.g., electrophysiological activity or cellular activity, is typically a “statistically significant” amount, 062460-503001WG and may include an increase that is 1.1, 1.2, 1.5. 2, 3, 4, 5, 6, 7, 8. 9, 10, 15, 20, 30 or more times (e.g., 500, 1000 times) (including all integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7. 1.8, etc.) the level of activity in an untreated cell.

[1077] The term “decrease’' or “reduced” amount of a physiological response, e.g., electrophysiological activity or cellular activity, is typically a “statistically significant” amount, and may include an decrease that is 1.1, 1.2, 1.5. 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more times (e.g., 500, 1000 times) (including all integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7. 1.8, etc.) the level of activity in an untreated cell.

[1078] The term “maintain,” or “preserve,” or “maintenance,” or “no change,” or “no substantial change.” or “no substantial decrease” refers generally to a physiological response that is comparable to a response caused by either vehicle, or a control molecule / composition. A comparable response is one that is not significantly different or measurable different from the reference response.

[1079] " Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides. The terms “polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term “nucleoside” refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non limiting examples, of nucleosides include, cytidine, uridine, adenosine, guanosine, thymidine and inosine. The term “nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxy ribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides contemplated herein include any ty pes of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA. genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term “duplex” in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.

[1080] Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable 062460-503001WG of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction.

[1081] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate. phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.; and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LN A) as known in the art), including those described in U. S. Patent Nos. 5,235,033 and 5,034.506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the intemucleotide linkages in DNA are phosphodiester, phosphodi ester derivatives, or a combination of both.

[1082] Nucleic acids can include nonspecific sequences. As used herein, the term "nonspecific sequence" refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.

[1083] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when the 062460-503001WG polynucleotide is RNA). Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and / or modified nucleotides.

[1084] The term “complement,” as used herein, refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanosine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. A further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.

[1085] As described herein the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other, may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region).

[1086] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxy proline, y-carboxy glutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a 062460-503001WG carboxyl group, an amino group, and an R group, e.g, homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring ammo acid’7and ■‘unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[1087] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[1088] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

[1089] An amino acid or nucleotide base "position" is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[1090] The terms "numbered with reference to" or "corresponding to," when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. An amino acid residue in a protein "corresponds" to a given 062460-503001WG residue when it occupies the same essential structural position within the protein as the given residue. One skilled in the art will immediately recognize the identity and location of residues corresponding to a specific position in a protein in other proteins with different numbering systems. For example, by performing a simple sequence alignment with a protein the identity7and location of residues corresponding to specific positions of the protein are identified in other protein sequences aligning to the protein. For example, a selected residue in a selected protein corresponds to glutamic acid at position 138 when the selected residue occupies the same essential spatial or other structural relationship as a glutamic acid at position 138. In some embodiments, where a selected protein is aligned for maximum homology with a protein, the position in the aligned selected protein aligning with glutamic acid 138 is the to correspond to glutamic acid 138. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g.. where the structure of the selected protein is aligned for maximum correspondence with the glutamic acid at position 138, and the overall structures compared. In this case, an amino acid that occupies the same essential position as glutamic acid 138 in the structural model is the to correspond to the glutamic acid 138 residue.

[1091] " Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, "conservatively modified variants" refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.

[1092] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in 062460-503001WG addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the disclosure.

[1093] The following eight groups each contain amino acids that are conservative substitutions for one another:

[1094] 1) Alanine (A), Glycine (G);

[1095] 2) Aspartic acid (D), Glutamic acid (E);

[1096] 3) Asparagine (N), Glutamine (Q);

[1097] 4) Arginine (R), Lysine (K);

[1098] 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);

[1099] 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);

[1100] 7) Serine (S), Threonine (T); and

[1101] 8) Cysteine (C), Methionine (M)

[1102] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity' over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g, NCBI web site at the World Wide Web (www) at ncbi.nlm.nih.gov / BLAST or the like). Such sequences are then said to be "substantially identical." This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity' exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.

[1103] " Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity. Percent identity' may also be determined, for example, by comparing 062460-503001WG sequence information using the advanced BLAST computer program, including version 2.2.9, available from the National Institutes of Health. The BLAST program is based on the alignment method of Karlin and Altschul, Proc. Natl. Acad. Sci. USA 87:2264-2268 (1990) and as discussed in Altschul, et al., J. Mol. Biol. 215:403-410 (1990); Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873-5877 (1993); and Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997). Briefly, the BLAST program defines identity as the number of identical aligned symbols (generally nucleotides or amino acids), divided by the total number of symbols in the shorter of the two sequences. The program may be used to determine percent identity over the entire length of the proteins being compared. Default parameters are provided to optimize searches with short query' sequences in. for example, with the blastp program. The program also allows use of an SEG filter to mask-off segments of the query sequences as determined by the SEG program of Wootton and Federhen, Computers and Chemistry 17:149-163 (1993). Ranges of desired degrees of sequence identity are approximately 80% to 100% and integer values therebetween. Typically, the percent identities between a disclosed sequence and a claimed sequence are at least 80%. at least 85%. at least 90%, at least 95%, or at least 98%.

[1104] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of, e.g., a full length sequence or from 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math.

[1105] 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol.

[1106] 48:443, by the search for similarity- method of Pearson and Lipman (1988) Proc. Nat 'I. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel el al., Current Protocols in Molecular Biology (1995 supplement)).

[1107] An example of an algorithm that is suitable for determining percent sequence identity and sequence similarity' are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402, and Altschul etal. (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (see, the World Wide Web (wwyv) at ncbi.nlm.nih.gov). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy' some positive-valued 062460-503001WG threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity' and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[1108] The BLAST algorithm also performs a statistical analysis of the similarity' between two sequences (see. e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787). One measure of similarity’ provided by the BLAST algorithm is the smallest sum probability' (P(N)), which provides an indication of the probability' by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[1109] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence. 062460-503001WG Antibodies are large, complex molecules (molecular weight of -150,000 or about 1320 amino acids) with intricate internal structure. A natural antibody molecule contains two identical pairs of polypeptide chains, each pair having one light chain and one heavy chain. Each light chain and heavy chain in turn consists of two regions: a variable (“V”) region, involved in binding the target antigen, and a constant (“C”) region that interacts with other components of the immune system. The light and heavy chain variable regions (also referred to herein as light chain variable (VL) domain and heavy chain variable (VH) domain, respectively) come together in 3-dimensional space to form a variable region that binds the antigen (for example, a receptor on the surface of a cell). Within each light or heavy chain variable region, there are three short segments (averaging 10 amino acids in length) called the complementarity determining regions (“CDRs”). The six CDRs in an antibody variable domain (three from the light chain and three from the heavy chain) fold up together in 3 -dimensional space to form the actual antibody binding site which docks onto the target antigen. The position and length of the CDRs have been precisely defined by Kabat, E. et al.. Sequences of Proteins of Immunological Interest, U. S. Department of Health and Human Services, 1983, 1987. The part of a variable region not contained in the CDRs is called the framework region, which forms the environment for the CDRs. In embodiments, the framework region is humanized.

[1110] An ‘‘antibody variant” as provided herein refers to a polypeptide capable of binding to an antigen and including one or more structural domains (e.g., light chain variable domain, heavy chain variable domain) of an antibody or fragment thereof. Non-limiting examples of antibody variants include single-domain antibodies or nanobodies, monospecific Fab2, bispecific Fab2, trispecific Fab;, monovalent IgGs, scFv, multivalent antibodies, multivalent diabodies, trispecific triabodies, scFv-Fc, minibodies, IgNAR. V-NAR, hcIgG, VHH. or peptibodies. A “peptibody” as provided herein refers to a peptide moiety attached (through a covalent or non-covalent linker) to the Fc domain of an antibody. Further non-limiting examples of antibody variants known in the art include antibodies produced by cartilaginous fish or camelids. A general description of antibodies from camelids and the variable regions thereof and methods for their production, isolation, and use may be found in references WO97 / 49805 and WO 97 / 49805 which are incorporated by reference herein in their entirety and for all purposes. Likewise, antibodies from cartilaginous fish and the variable regions thereof and methods for their production, isolation, and use may be found in W02005 / 118629, which is incorporated by reference herein in its entirety and for all purposes.

[1111] The terms " CDR LI", " CDR L2" and " CDR L3" as provided herein refer to the complementarity determining regions (CDR) 1, 2, and 3 of the variable light (L) chain of an antibody. In embodiments, the variable light chain provided herein includes in N-terminal to C- 062460-503001WG terminal direction a CDR LI, a CDR L2 and a CDR L3. Likewise, the terms " CDR Hl", " CDR H2" and " CDR H3" as provided herein refer to the complementarity determining regions (CDR) 1, 2, and 3 of the variable heavy (H) chain of an antibody. In embodiments, the variable heavy chain provided herein includes in N-terminal to C-terminal direction a CDR Hl, a CDR H2 and a CDR H3.

[1112] The terms " FR LI". " FR L2", " FR L3" and " FR L4" as provided herein are used according to their common meaning in the art and refer to the framework regions (FR) 1, 2, 3 and 4 of the variable light (L) chain of an antibody. In embodiments, the variable light chain provided herein includes in N-terminal to C-terminal direction a FR LI, a FR L2, a FR L3 and a FR L4. Likewise, the terms " FRH1". " FRH2". " FRH3" and " FRH4" as provided herein are used according to their common meaning in the art and refer to the framework regions (FR) 1, 2, 3 and 4 of the variable heavy (H) chain of an antibody. In embodiments, the variable heavy chain provided herein includes in N-terminal to C-terminal direction a FR Hl, a FR H2, a FR H3 and a FR H4. In embodiments, the framework region is humanized.

[1113] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL), variable light chain (VL) domain or light chain variable region and variable heavy chain (VH), variable heavy chain (VH) domain or heavy chain variable region refer to these light and heavy chain regions, respectively. The terms variable light chain (VL), variable light chain (VL) domain and light chain variable region as referred to herein may be used interchangeably. The terms variable heavy chain (VH). variable heavy chain (VH) domain and heavy chain variable region as referred to herein may be used interchangeably. The Fc (i.e. fragment crystallizable region) is the "base" or "tail" of an immunoglobulin and is typically composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody. By binding to specific proteins, the Fc region ensures that each antibody generates an appropriate immune response for a given antigen. The Fc region also binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins.

[1114] The term "antibody" is used according to its commonly known meaning in the art. Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CHI by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer 062460-503001WG into an Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990)). The term “antibody” as referred to herein further includes antibody variants such as single domain antibodies. Thus, in embodiments an antibody includes a single monomeric variable antibody domain. Thus, in embodiments, the antibody, includes a variable light chain (VL) domain or a variable heavy chain (VH) domain. In embodiments, the antibody is a variable light chain (VL) domain or a variable heavy chain (VH) domain.

[1115] For preparation of monoclonal or polyclonal antibodies, any technique known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today ^'. Tl (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy (1985)). " Monoclonal" antibodies (mAb) refer to antibodies derived from a single clone. Techniques for the production of single chain antibodies (U. S. Pat. No. 4,946,778) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized antibodies. Alternatively, phage display technology7can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)).

[1116] A single-chain variable fragment (scFv) is typically a fusion protein of the variable regions of the heavy' (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of 10 to about 25 amino acids. The linker may usually be rich in glycine for flexibility7, as well as serine or threonine for solubility. The linker can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa. The linker can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa.

[1117] A “diabody” is used according to its ordinary' meaning in the art and refers to an scFv dimer including the varable heavy (VH) and variable light (VL) regions of an antibody, where the dimers are donnected by a linker.

[1118] The epitope of a mAb is the region of its antigen to which the mAb binds. Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a lx, 5x, lOx, 20x or lOOx excess of one antibody inhibits binding of the 062460-503001WG other by at least 30% but preferably 50%. 75%. 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans etal., Cancer Res. 50:1495, 1990). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.

[1119] By ‘'detuned” is a variant of an antibody or domain thereof (e g., VH, VH, VHH, or CDR) that has reduced affinity for its target due to one or more mutations in its amino acid sequence. Illustrative detuned anti-HSA VHH domains having reduced capacity for binding HSA due to one or more mutations relative to a wild type anti-HSA VHH, are shown in Table 11 and comprises a sequence at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 941 to 988, e.g., 958, 977, and 983. Specific useful mutations are found in Table 17. In some cases, the wild type anti-HSA VHH has the sequence of SEQ ID NO: 940.

[1120] For preparation of suitable antibodies of the invention and for use according to the invention, e.g., recombinant, monoclonal, or polyclonal antibodies, many techniques known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al.. Immunology Today 4: 72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane. Antibodies, A Laboratory Manual (1988): and Goding. Monoclonal Antibodies: Principles and Practice (2d ed. 1986)). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy’ and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed.

[1121] 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U. S. Patent 4,946,778, U. S. Patent No. 4,816,567) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U. S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg & Huszar, Intern. Rev. Immunol. 13:65-93 (1995)). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., 062460-503001WG Biotechnology 10:779-783 (1992)). Antibodies can also be made multivalent, i.e., able to recognize two or more different antigens (see, e.g., WO 93 / 08829, Traunecker et al., EMBO J.

[1122] 10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121:210 (1986)). Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U. S. Patent No. 4,676.980, WO 91 / 00360; WO 92 / 200373; and EP 03089).

[1123] As used herein, the term “multivalent”, “multivalent antibody”, or “mvAb” means an antibody or antibody fragment that is able to recognize two or more different antigens, e.g., two, three, four, or more diffemet antigens. An example of a multivalent antibody is a bispecific antibody (“bsAb”) that recognizes two diffemet antigens, e.g., PD1 and CD2. Another example of a multivalent antibody is a trispecific (“tsAb”) antibody that recognizes three diffemet antigens, e.g., PD1, CD2, and HSA.

[1124] Methods for humanizing or primatizing non-human antibodies are well known in the art (e.g., U. S. Patent Nos. 4,816,567; 5,530,101; 5,859,205; 5,585,089; 5,693,761; 5,693,762; 5.777,085; 6,180,370; 6,210.671; and 6,329.511; WO 87 / 02671; EP Patent Application 0173494; Jones et al. (1986) Nature 321:522; and Verhoyen et al. (1988) Science 239:1534). Humanized antibodies are further described in, e g., Winter and Milstein (1991) Nature 349:293. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers (see, e.g., Morrison et al., PNAS USA, 81:6851-6855 (1984), Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv. Immunol., 44:65-92 (1988), Verhoeyen et al., Science 239:1534-1536 (1988) and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992), Padlan. Molec. Immun., 28:489-498 (1991); Padlan, Molec. Immun., 31(3): 169-217 (1994)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric antibodies (U. S. Patent No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. For example, polynucleotides comprising a first sequence coding for humanized immunoglobulin framework regions and a second sequence set coding for the desired immunoglobulin complementarity determining regions can be produced synthetically or by combining appropriate cDNA and genomic DNA segments. Human constant region DNA sequences can be isolated in accordance with well know n procedures from a variety of human cells. 062460-503001WG A "chimeric antibody" is an antibody molecule in which (a) the constant region, or aportion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and / or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity. The preferred antibodies of, and for use according to the invention include humanized and / or chimeric monoclonal antibodies.

[1125] The phrase "specifically (or selectively) binds" to an antibody or "specifically (or selectively) immunoreactive with." when referring to a protein or peptide, refers to a binding reaction that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologies. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times the background and more typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only a subset of antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).

[1126] A "ligand" refers to an agent, e.g., a polypeptide or other molecule, capable of binding to a receptor or antibody, antibody variant, antibody region or fragment thereof.

[1127] Techniques for conjugating therapeutic agents to antibodies are well known (see, e.g., Amon et al., " Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss. Inc.

[1128] 1985); Hellstrom et al., “Antibodies For Drug Delivery”in Controlled Drug Delivery (2ndEd ), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, " Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review" in Monoclonal Antibodies ‘84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); and Thorpe et al.. " The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev., 62: H SS (1982)). As used herein, the term “antibody -drug conjugate” or “ADC” refers to a therapeutic agent conjugated or otherwise covalently bound to to an antibody. 062460-503001WD A " PD-1 protein" as referred to herein includes any of the recombinant or naturally-occurring forms of the Programmed cell death protein 1 (PD-1) protein, also known as protein PD-1 or PD1, or variants or homologs thereof that maintain PD-1 activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity' compared to PD1). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring PD-1 protein. In embodiments, the PD-1 protein is substantially identical to the protein identified by the UniProt reference number Q15116 or a variant or homolog having substantial identity thereto.

[1129] A " PD-L1 protein" as referred to herein includes any of the recombinant or naturally-occurring forms of the Programmed cell death 1 ligand 1 (PD-L1) protein, also known as PDL1, PDCD1 ligand 1; Programmed death ligand l; hPD-Ll, CD274, B7 homolog 1 or variants or homologs thereof that maintain PDL1 activity' (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to PDL1). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring PDL1 protein. In embodiments, the PD-L1 protein is substantially identical to the protein identified by the UniProt reference number Q9NZQ7 or a variant or homolog having substantial identity thereto.

[1130] For specific proteins described herein, the named protein includes any of the protein’s naturally occurring forms, variants or homologs that maintain the protein transcription factor activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity' compared to the native protein). In some embodiments, variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring form. In other embodiments, the protein is the protein as identified by its NCBI sequence reference. In other embodiments, the protein is the protein as identified by its NCBI sequence reference, homolog or functional fragment thereof.

[1131] The term "gene" means the segment of DNA involved in producing a protein; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons). The leader, the trailer as well as the introns include regulatory’ elements that are necessary during the transcription and the translation of a gene. Further, a "protein gene product" is a protein expressed from a particular gene. 062460-503001WG The terms "plasmid", "vector" or "expression vector" refer to a nucleic acid molecule that encodes for genes and / or regulatory elements necessary for the expression of genes. Expression of a gene from a plasmid can occur in cis or in trans. If a gene is expressed in cis, the gene and the regulator}' elements are encoded by the same plasmid. Expression in trans refers to the instance where the gene and the regulatory elements are encoded by separate plasmids.

[1132] The terms "transfection", "transduction", "transfecting" or "transducing" can be used interchangeably and are defined as a process of introducing a nucleic acid molecule or a protein to a cell. Nucleic acids are introduced to a cell using non-viral or viral-based methods. The nucleic acid molecules may be gene sequences encoding complete proteins or functional portions thereof. Non-viral methods of transfection include any appropriate transfection method that does not use viral DNA or viral particles as a delivery system to introduce the nucleic acid molecule into the cell. Exemplary' non-viral transfection methods include calcium phosphate transfection, liposomal transfection, nucleofection, sonoporation, transfection through heat shock, magnetifection and electroporation. In some embodiments, the nucleic acid molecules are introduced into a cell using electroporation following standard procedures well known in the art. For viral-based methods of transfection any useful viral vector may7be used in the methods described herein. Examples for viral vectors include, but are not limited to retroviral, adenoviral, lentiviral and adeno-associated viral vectors. In some embodiments, the nucleic acid molecules are introduced into a cell using a retroviral vector following standard procedures well known in the art. The terms "transfection" or "transduction" also refer to introducing proteins into a cell from the external environment. Typically, transduction or transfection of a protein relies on attachment of a peptide or protein capable of crossing the cell membrane to the protein of interest. See, e.g., Ford et al. (2001) Gene Therapy 8: 1-4 and Prochiantz (2007) Nat. Methods 4:119-20.

[1133] A "label" or a "detectable moiety" is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include 32P, fluorescent dyes, electron-dense reagents, enzy mes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. Any appropriate method known in the art for conjugating an antibody to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.

[1134] When the label or detectable moiety is a radioactive metal or paramagnetic ion, the agent may be reacted with another long-tailed reagent having a long tail with one or more chelating groups attached to the long tail for binding to these ions. The long tail may be a polymer such as a polylysine, polysaccharide, or other derivatized or derivatizable chain having pendant groups to 062460-503001WG which the metals or ions may be added for binding. Examples of chelating groups that may be used according to the disclosure include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTP A), DOTA, NOTA, NETA, TETA, porphyrins, polyamines, crown ethers, bis-thiosemicarbazones, polyoximes, and like groups. The chelate is normally linked to the PSMA antibody or functional antibody fragment by a group, which enables the formation of a bond to the molecule with minimal loss of immunoreactivity and minimal aggregation and / or internal cross-linking. The same chelates, when complexed with nonradioactive metals, such as manganese, iron and gadolinium are useful for MRI, when used along with the antibodies and carriers described herein. Macrocyclic chelates such as NOTA, DOTA, and TETA are of use with a variety of metals and radiometals including, but not limited to, radionuclides of gallium, yttrium and copper, respectively. Other ring-type chelates such as macrocyclic polyethers, which are of interest for stably binding nuclides, such as 223Ra for RAIT may be used. In certain embodiments, chelating moieties may be used to attach a PET imaging agent, such as an A1-18F complex, to a targeting molecule for use in PET analysis.

[1135] " Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. antibodies and antigens) to become sufficiently proximal to react, interact, or physically touch. It should be appreciated; however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[1136] The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be, for example, a pharmaceutical composition as provided herein and a cell. In embodiments contacting includes, for example, allowing a pharmaceutical composition as described herein to interact with a cell (e.g. a T cell).

[1137] A "cell" as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells.

[1138] The term "recombinant" when used with reference, e.g., to a cell, nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that 062460-503001WG the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all. Transgenic cells and plants are those that express a heterologous gene or coding sequence, ty pically as a result of recombinant methods.

[1139] The term "isolated", when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography’. A protein that is the predominant species present in a preparation is substantially purified.

[1140] The term "heterologous" when used w ith reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes...

Claims

062460-503001WG CLAIMSWhat is claimed is:

1. A multivalent antibody comprising at least one anti-PD-1 antibody region and at least one anti-CD2 antibody region.

2. The multivalent antibody of claim 1, wherein the multivalent antibody recognizes and binds to a PD-1 antigen and to a CD2 antigen on an effector cell.

3. The multivalent antibody of claim 2, wherein the effector cell is a CD8+ T cell (e g., a CD8+ CD4- T cell), a CD4+ T cell (e.g., a CD8- CD4+ T cell), a gamma delta (y5) T cell, an invariant T cell, a natural killer (NK) cell, an invariant natural killer cell (iNK cell), an invariant natural killer T cell (iNKT cell), or a macrophage.

4. The multivalent antibody of claim 3, wherein the effector cell is a T cell.

5. The multivalent antibody of claim 4, wherein the T cell is a CD4+ T cell or a CD8+ T cell.

6. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell promotes PD-1 activation.

7. The multivalent antibody of any one of claims 2 to 5, wherein the multivalent antibody does not disrupt binding to the CD2 ligand CD58 on the effector cell.

8. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell promotes recruitment of PD-1 / CD2 complexes to the immunological synapse by CD58 expressed on antigen presenting cells.

9. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to CD2 antigens on the effector cell recruits PD-1 to the synapse by bridging it in cis to the costimulatory receptor CD2.

10. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell stimulates PD-1 phosphorylation and association with the T cell-inhibiting phosphatase SHP2.

11. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell modulates the signaling pathways downstream of CD2.

12. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell inhibits effector cell proliferation.

13. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell decreases IL-2 production and / or IFN-y production by the effector cell.

14. The multivalent antibody of any one of claims 2 to 5, wherein the multivalent antibody does not induce pro-inflammatory pathways by the effector cell via FcR engagement.062460-503001WG 15. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell suppresses IFNy expression from antigen stimulated PBMCs irrespective of FcR genotype.

16. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell inhibits the effector cell and / or activates immunomodulatory signals to the effector cell.

17. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell reduces the effector cell’s cytotoxic response towards an autologous cell.

18. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell provides greater inhibition effector cell activity, promotion of immunomodulatory signals, and / or reduced effector cell proliferation relative to a monospecific anti-PD-1 antibody.

19. The multivalent antibody of any one of claims 2 to 5, wherein the multivalent antibody provides greater PD-1 receptor occupancy and / or PD-1 blockade than the monospecific anti- PD-1 antibody.

20. The multivalent antibody of any one of claims 2 to 5, wherein binding of the multivalent antibody to antigens on the effector cell suppresses and prevents disease progression in graft- versus-host disease (GVHD).

21. The multivalent antibody of any one of claims 1 to 20, wherein the multivalent antibody comprises an antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a sequence show n in one or more of Table 1 to Table 11.

22. The multivalent antibody of any one of claims 1 to 21. wherein the multivalent antibody comprises an antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a sequence shown in one or more of Table 1 to Table 3 and a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a sequence shown in one or more of Table 4 to Table 7.

23. The multivalent antibody of any one of claims 1 to 22. wherein the multivalent antibody comprises a sequence that is at least 90% identical (e g., 95%, 99%, or 100% identical) to a sequence show n in Table 8.

24. The multivalent antibody of any one of claims 1 to 22, w herein the multivalent antibody comprises a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a sequence shown in Table 9.062460-503001WG 25. The multivalent antibody of any one of claims 1 to 22. wherein the multivalent antibody comprises a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a sequence shown in Table 10.

26. The multivalent antibody of any one of claims 1 to 25, wherein the multivalent antibody comprises an antibody region comprising one to six complementarity’ determining regions (‘ CDRs’ ) sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the CDR sequence shown in Table 1.

27. The multivalent antibody of claim 26, wherein the multivalent antibody comprises an antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) sequences from a single row of Table 1.

28. The multivalent antibody of claims 26-27, wherein the multivalent antibody comprises an antibody region comprising three Light Chain CDRs (CDR-L1, CDR-L2, and CDR-L3) sequences from a single row of Table 1.

29. The multivalent antibody of any one of claims 26 to 28, wherein the multivalent antibody comprises an antibody region comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences from a single row of Table 1.

30. The multivalent antibody of any one of claims 1 to 29, wherein the multivalent antibody comprises an antibody region comprising one or more Variable Heavy (VH) sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VH sequences shown in Table 2.

31. The multivalent antibody of any one of claims 1 to 30, wherein the multivalent antibody comprises an antibody region comprising one or more Variable Light (VL) sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VL sequences shown in Table 2.

32. The multivalent antibody of any one of claims 1 to 31, wherein the multivalent antibody comprises an antibody region comprising one or more VH sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VH sequences shown in Table 2 and one or more VL sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VL sequences shown in Table 2.

33. The multivalent antibody of any one of claims 1 to 32, wherein the multivalent antibody comprises an antibody region comprising a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 2, and one VL sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VL sequence shown in the single row of Table 2.062460-503001WG 34. The multivalent antibody of any one of claims 1 to 33. wherein the multivalent antibody comprises an antibody region comprising one or more VHH sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VHH sequences shown in Table 3.

35. The multivalent antibody of any one of claims 1 to 34, wherein an anti-CD2 antibody region is configured as a Fab, a single-chain variable fragment (scFv), and / or a single variable domain on a heavy chain (VHH).

36. The multivalent antibody of claim 35, wherein the anti-CD2 antibody region is configured as an scFv and comprises an antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to sequences as shown in Table 1 or Table 2.

37. The multivalent antibody of any one of claims 1 to 36, wherein the multivalent antibody comprises at least two anti-CD2 antibody regions.

38. The multivalent antibody of any one of claims 1 to 37, wherein the multivalent antibody comprises at least three anti-CD2 antibody regions.

39. The multivalent antibody of any one of claims 21 to 38, wherein a multivalent antibody comprising a sequence that is less than 100% identical to a sequence shown in one or more of Table 1 to Table 3 or Table 8 retains affinity for CD2 that is substantially equivalent to a multivalent antibody comprising a sequence that is 100% identical to a sequence shown in one or more of Table 1 to Table 3 or Table 8.

40. The multivalent antibody of any one of claims 21 to 38, wherein a multivalent antibody comprising a sequence that is less than 100% identical to a sequence show n in one or more of Table 1 to Table 3 or Table 8 has less affinity for CD2 than a multivalent antibody comprising a sequence that is 100% identical to a sequence shown in one or more of Table 1 to Table 3 or Table 8.

41. The multivalent antibody of any one of claims 1 to 40, wherein the multivalent antibody comprises an antibody region comprising one to six complementarity determining regions (“CDRs ’) sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the CDR sequence shown in Table 4 or Table 5.

42. The multivalent antibody of claim 41, wherein the multivalent antibody comprises an antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) sequences from a single row of Table 4 or Table 5.

43. The multivalent antibody of claims 41 to 42. wherein the multivalent antibody comprises an antibody region comprising three Light Chain CDRs (CDR-L1, CDR-L2, and CDR-L3) sequences from a single row of Table 4 or Table 5.062460-503001WG 44. The multivalent antibody of any one of claims 41 to 43, wherein the multivalent antibody comprises an antibody region comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences from a single row of Table 4 or Table 5.

45. The multivalent antibody of any one of claims 1 to 44, wherein the multivalent antibody comprises an antibody region comprising one or more Variable Heavy (VH) sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VH sequences shown in Table 6.

46. The multivalent antibody of any one of claims 1 to 45, wherein the multivalent antibody comprises an antibody region comprising one or more Variable Light (VL) sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VL sequences shown in Table 6.

47. The multivalent antibody of any one of claims 1 to 46, wherein the multivalent antibody comprises an antibody region comprising one or more VH sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VH sequences shown in Table 6 and one or more VL sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VL sequences shown in Table 6.

48. The multivalent antibody of any one of claims 1 to 47, wherein the multivalent antibody comprises an antibody region comprising a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 6 and one VL sequence that is at least 90% identical (e g., 95%, 99%, or 100% identical) to a VL sequence shown in the single row of Table 6.

49. The multivalent antibody of any one of claims 1 to 48, wherein the multivalent antibody comprises an antibody region comprising one or more VHH sequences that are at least 90% identical (e.g., 95%, 99%, or 100% identical) to the VHH sequences shown in Table 7.

50. The multivalent antibody of any one of claims 1 to 49, wherein an anti-PD- 1 antibody region is configured as a Fab, a single-chain variable fragment (scFv), and / or a single variable domain on a heavy chain (VHH).

51. The multivalent antibody of claim 50, wherein the anti-PD- 1 antibody region is configured as an scFv and comprises an antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to sequences shown in Table 4 to Table 6.

52. The multivalent antibody of any one of claims 1 to 51, wherein the multivalent antibody comprises at least two anti-PD-1 antibody regions.

53. The multivalent antibody of any one of claims 1 to 52, wherein the multivalent antibody comprises at least three anti-PD-1 antibody regions.062460-503001WG 54. The multivalent antibody of any one of claims 41 to 53, wherein a multivalent antibody comprising a sequence that is less than 100% identical to a sequence shown in one or more of Table 4 to Table 8 retains affinity for PD-1 that is substantially equivalent to a multivalent antibody comprising a sequence that is 100% identical to a sequence shown in one or more of Table 4 to Table 8.

55. The multivalent antibody of any one of claims 41 to 53, wherein a multivalent antibody comprising a sequence that is less than 100% identical to a sequence shown in one or more of Table 4 to Table 8 has less affinity for PD-1 than a multivalent antibody comprising a sequence that is 100% identical to a sequence shown in one or more of Table 4 to Table 8.

56. The multivalent antibody of any one of claims 1 to 55. wherein the multivalent antibody comprises a first antibody region comprising CDR-H1, CDR-H2, and CDR-H3 sequences from a single row of Table 1, and comprises a second antibody region comprising CDR-H1, CDR-H2, and CDR-H3 sequences from a single row of Table 4 or Table 5.

57. The multivalent antibody of any one of claims 1 to 56. wherein the multivalent antibody comprises a third antibody region comprising CDR-H1, CDR-H2, and CDR-H3 sequences from a single row of Table 1, and / or comprises a fourth antibody region comprising CDR-H1, CDR-H2, and CDR-H3 sequences from a single row of Table 4 or Table 5.

58. The multivalent antibody of any one of claims 1 to 57, wherein the multivalent antibody comprises a first antibody region comprising CDR-H1. CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3 sequences from a single row of Table 1 and comprises a second antibody region comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences from a single row of Table 4 or Table 5.

59. The multivalent antibody of any one of claims 1 to 58. wherein the multivalent antibody comprises a third antibody region comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3 sequences from a single row of Table 1 and / or comprises a fourth antibody region comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences from a single row of Table 4 or Table 5.

60. The multivalent antibody of any one of claims 1 to 59. wherein the multivalent antibody comprises a first antibody region comprising a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in Table 2 and comprises a second antibody region comprising a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in Table 6.

61. The multivalent antibody of any one of claims 1 to 60, wherein the multivalent antibody comprises a third antibody region comprising a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in Table 2 and / or comprises a062460-503001WG fourth antibody region comprising a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in Table 6.

62. The multivalent antibody of any one of claims 1 to 61, wherein the multivalent antibody comprises a first antibody region comprising a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 2 and one VL sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VL sequence shown in the single row of Table 2 and comprises a second antibody region comprising a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 6 and one VL sequence that is at least 90% identical (e.g.. 95%, 99%. or 100% identical) to a VL sequence shown in the single row of Table 6.

63. The multivalent antibody of any one of claims 1 to 62, wherein the multivalent antibody comprises a third antibody region comprising a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row of Table 2 and one VL sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VL sequence shown in the single row of Table 2 and / or comprises a fourth antibody region comprising a VH sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to a VH sequence shown in a single row- of Table 6 and one VL sequence that is at least 90% identical (e.g.. 95%. 99%. or 100% identical) to a VL sequence shown in the single row of Table 6.

64. The multivalent antibody of any one of claims 1 to 63, wherein the multivalent antibody comprises a first antibody region configured as an scFv and comprises an antibody region comprising a sequence that is at least 90% identical (e.g.. 95%. 99%. or 100% identical) to sequences as shown in Table 1 or Table 2 and / or comprises a second antibody configured as an scFv and comprises an antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to sequences shown in Table 4 to Table 6.

65. The multivalent antibody of any one of claims 1 to 64, wherein the multivalent antibody comprises a third antibody region configured as an scFv and comprises an antibody region comprising a sequence that is at least 90% identical (e g., 95%, 99%, or 100% identical) to sequences as shown in Table 1 or Table 2 and / or comprises a fourth antibody region configured as an scFv and comprises an antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to sequences shown in Table 4 to Table 6.

66. The multivalent antibody of any one of claims 1 to 65, wherein the multivalent antibody comprises a first antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to sequences shown in Table 3 and / or comprises a second062460-503001WG antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to sequences shown in Table 7.

67. The multivalent antibody of any one of claims 1 to 66, wherein the multivalent antibody comprises a third antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to sequences shown in Table 3 and / or comprises a fourth antibody region comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to sequences shown in Table 7.

68. The multivalent antibody of any one of claims 1 to 67, wherein the multivalent antibody comprises one or more Fabs, comprises one or more scFvs, and / or comprises one or more VHHs.

69. The multivalent antibody of any one of claims 1 to 68, wherein the multivalent antibody comprises at least two Fabs.

70. The multivalent antibody of claim 69, wherein a first Fab comprises an anti-PD-1 antibody region and a second Fab comprises an anti-CD2 antibody region.

71. The multivalent antibody of any one of claims 1 to 68, wherein the multivalent antibody comprises at least one Fab and at least one VHH.

72. The multivalent antibody of claim 71, wherein the at least one Fab comprises an anti-PD- 1 antibody region and the at least one VHH comprises an anti-CD2 antibody region.

73. The multivalent antibody of claim 71, wherein the at least one Fab comprises an anti- CD2 antibody region and the at least one VHH comprises an anti-PDl antibody region.

74. The multivalent antibody of any one of claims 1 to 68, wherein the multivalent antibody comprises at least one Fab and at least one scFv.

75. The multivalent antibody of claim 74, wherein the at least one Fab comprises an anti-PD- 1 antibody region and the at least one scFv comprises an anti-CD2 antibody region.

76. The multivalent antibody of claim 74, wherein the at least one Fab comprises an anti- CD2 antibody region and the at least one scFv comprises an anti-PDl antibody region.

77. The multivalent antibody of any one of claims 1 to 68, wherein the multivalent antibody comprises at least two Fabs and comprises at least one VHH.

78. The multivalent antibody of claim 77, wherein both Fabs comprise an anti-PD-1 antibody region.

79. The multivalent antibody of claim 77, wherein both Fabs comprise an anti-CD2 antibody region.

80. The multivalent antibody of claim 77, wherein a first Fab comprises an anti-PD-1 antibody region and a second Fab comprises an anti-CD2 antibody region.062460-503001WG 81. The multivalent antibody of any one of claims 77 to 80, wherein the at least one VHH comprises an anti-PD-1 antibody region.

82. The multivalent antibody of any one of claims 77 to 80, wherein the at least one VHH comprises an anti-CD2 antibody region.

83. The multivalent antibody of any one of claims 1 to 68. wherein the multivalent antibody comprises at least two Fabs and comprises at least one scFv.

84. The multivalent antibody of claim 83, wherein both Fabs comprise an anti-PD-1 antibody region.

85. The multivalent antibody of claim 83, wherein both Fabs comprise an anti-CD2 antibody region.

86. The multivalent antibody of claim 83, wherein a first Fab comprises an anti-PD-1 antibody region and a second Fab comprises an anti-CD2 antibody region.

87. The multivalent antibody of any one of claims 83 to 86, wherein the at least one scFv comprises an anti-PD-1 antibody region.

88. The multivalent antibody of any one of claims 83 to 86, wherein the at least one scFv comprises an anti-CD2 antibody region.

89. The multivalent antibody of any one of claims 1 to 68, wherein the multivalent antibody comprises at least two Fabs and comprises at least two VHHs.

90. The multivalent antibody of claim 89, wherein both Fabs comprise an anti-PD-1 antibody¬ region.

91. The multivalent antibody of claim 89, wherein both Fabs comprise an anti-CD2 antibody region.

92. The multivalent antibody of claim 89, wherein a first Fab comprises an anti-PD-1 antibody region and a second Fab comprises an anti-CD2 antibody region.

93. The multivalent antibody of any one of claims 89 to 92, wherein both VHHs comprise an anti-PD-1 antibody region.

94. The multivalent antibody of any one of claims 89 to 92, wherein both VHHs comprise an anti-CD2 antibody region.

95. The multivalent antibody of any one of claims 89 to 92, wherein one VHH comprises an anti-PD-1 antibody region and one VHH comprises an anti-CD2 antibody region.

96. The multivalent antibody of any one of claims 1 to 68, wherein the multivalent antibody comprises at least two Fabs and comprises at least two scFvs.

97. The multivalent antibody of claim 96, wherein both Fabs comprise an anti-PD-1 antibody region.062460-503001WG 98. The multivalent antibody of claim 96, wherein both Fabs comprise an anti-CD2 antibody region.

99. The multivalent antibody of claim 96, wherein a first Fab comprises an anti-PD-1 antibody region and a second Fab comprises an anti-CD2 antibody region.

100. The multivalent antibody of any one of claims 96 to 99, wherein both scFvs comprise an anti-PD-1 antibody region.

101. The multivalent antibody of any one of claims 96 to 99, wherein both scFvs comprise an anti-CD2 antibody region.

102. The multivalent antibody of any one of claims 96 to 99, wherein one scFv comprises an anti-PD-1 antibody region and one scFv comprises an anti-CD2 antibody region.

103. The multivalent antibody of any one of claims 1 to 68, wherein the multivalent antibody comprises at least two VHHs.

104. The multivalent antibody of claim 103, wherein one VHH comprises an anti-PD-1 antibody region and one VHH comprises an anti-CD2 antibody region.

105. The multivalent antibody of any one of claims 103-104, wherein the multivalent antibody comprises at least three VHHs106. The multivalent antibody of any one of claims 103-105, wherein a first VHH comprises an anti-PD-1 antibody region, a second VHH comprises an anti-CD2 antibody region, and a third VHH comprises an anti-HSA antibody region.

107. The multivalent antibody of any one of claims 103-106, wherein the VHH comprising the anti-PD-1 antibody region is N-terminal to one or both of the VHH comprising the anti-CD2 antibody region and / or the VHH comprising the anti-HSA antibody region.

108. The multivalent antibody of any one of claims 103-106, wherein the VHH comprising the anti-CD2 antibody region is N-terminal to one or both of the VHH comprising the anti- PD-1 antibody region and / or the VHH comprising the anti-HSA antibody region.

109. The multivalent antibody of any one of claims 103-106, wherein the VHH comprising the anti-HSA antibody region is N-terminal to one or both of the VHH comprising the anti- PD-1 antibody region and / or the VHH comprising the anti-CD2 antibody region.

110. The multivalent antibody of any one of claims 103-109, wherein the multivalent antibody comprises a configuration, progressing N-terminal to C-terminal, of PD1: CD2: HSA;PD1: HSA: CD2; CD2: PD1: HSA; HSA: PD1: CD2; HSA: CD2: PD1; or CD2: HSA: PD1.

111. The multivalent antibody of any one of claims 106-110, wherein the VHH comprising the anti-HSA antibody region comprises three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 998 (GFTFSSFG), SEQ ID NO: 999 (ISGSGSDT), and SEQ ID NO: 1000 (TIGGGLSR) respectively.062460-503001WG 112. The multivalent antibody of any one of claims 106-110, wherein the VHH comprising the anti-HSA antibody region comprises three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 1001 (GFTFRSFG), SEQ ID NO: 1002 (ISGSGSDT), and SEQ ID NO: 1003 (TISGSLSR) respectively.

113. The multivalent antibody of any one of claims 106-110, wherein the VHH comprising the anti-HSA antibody region comprises three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 1004 (GFTFRSFG), SEQ ID NO: 1005 (ISGSGSDT), and SEQ ID NO: 1006 (TIGGVLSR) respectively.

114. The multivalent antibody of any one of claims 106-110, wherein the VHH comprising the anti-HSA antibody region comprises three Heavy Chain CDRs (CDR-H1, CDR-H2. and CDR-H3) compnsing SEQ ID NO: 1007 (GFTFSSFG), SEQ ID NO: 1008 (ISGSGSDT), and SEQ ID NO: 1009 (GGGLSR) respectively.

115. The multivalent antibody of any one of claims 106-114, wherein the VHH comprising the anti-HSA antibody region detuned in that it comprises one or more mutations relative to a wild type anti-HSA VHH (e.g., SEQ ID NO: 940) such that it has reduced affinity to HSA.

116. The multivalent antibody of any one of claims 106-115, wherein the VHH comprising the anti-HSA antibody region detuned in that it comprises two or more mutations, three or more mutations, four or more mutations, or five or more mutations relative to a wild type anti-HSA VHH (e.g., SEQ ID NO: 940) such that it has reduced affinity to HSA.

117. The multivalent antibody of any one of claims 106-116, wherein the VHH comprising the anti-HSA antibody region comprises a sequence at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 941 to 988, e.g., 958, 977, and 983.

118. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, and an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO:

407. and SEQ ID NO: 408 respectively.

119. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR- Hl, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, a constant region that is at least 90% identical (e.g., 95%, 99%, or062460-503001WG 100% identical) to SEQ ID NO: 780, and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 781.

120. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR- Hl, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780, and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 782.

121. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751 and an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604.

122. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region that is at least 90% identical (e g., 95%, 99%, or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO:

780. and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 781.

123. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%. or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780, and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 782.

124. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR- Hl, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region comprising three Heavy Chain CDRs062460-503001WG (CDR-H1. CDR-H2, and CDR-H3) comprising SEQ ID NO: 998 (GFTFSSFG). SEQ ID NO: 999 (ISGSGSDT), and SEQ ID NO: 1000 (TIGGGLSR) respectively.

125. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR- Hl, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 1001 (GFTFRSFG), SEQ ID NO: 1002 (ISGSGSDT), and SEQ ID NO: 1003 (TISGSLSR) respectively.

126. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR- Hl, CDR-H2, and CDR-H3) compnsing SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 1004 (GFTFRSFG), SEQ ID NO: 1005 (ISGSGSDT), and SEQ ID NO: 1006 (TIGGVLSR) respectively.

127. The multivalent antibody of any one of claims 1-20. wherein the multivalent antibody comprises an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR- Hl, CDR-H2, and CDR-H3) comprising SEQ ID NO:

406. SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 1007 (GFTFSSFG), SEQ ID NO: 1008 (ISGSGSDT), and SEQ ID NO: 1009 (GGGLSR) respectively.

128. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR- Hl, CDR-H2, and CDR-H3) compnsing SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region that is at least 90% identical (e.g.. 95%, 99%, or 100% identical) to SEQ ID NO: 958.

129. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1,062460-503001WG CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR- Hl, CDR-H2, and CDR-H3) comprising SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 977.

130. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region comprising three Heavy Chain CDRs (CDR-H1, CDR-H2, and CDR-H3) comprising SEQ ID NO: 652, SEQ ID NO: 653, and SEQ ID NO: 654 respectively, an anti-CD2 antibody region comprising three Heavy Chain CDRs (CDR- Hl, CDR-H2, and CDR-H3) comprising SEQ ID NO:

406. SEQ ID NO: 407, and SEQ ID NO: 408 respectively, and an anti HSA antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 983.

131. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 781, and an anti HSA antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 958.

132. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 781, and an anti HSA antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 977.

133. The multivalent antibody of any one of claims 1-20, wherein the multivalent antibody comprises an anti-PD-1 antibody region that is at least 90% identical (e.g.. 95%. 99%. or 100% identical) to SEQ ID NO: 751, an anti-CD2 antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 604, a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 781, and an anti HSA antibody region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 983.062460-503001WG 134. The multivalent antibody of any one of claims 128-133, wherein the anti-PD-1 antibody region is N-terminal to one or both of the anti-CD2 antibody region and / or the anti-HS A antibody region.

135. The multivalent antibody of any one of claims 128-133, wherein the anti-CD2 antibody¬ region is N-terminal to one or both of the anti- PD-1 antibody region and / or the anti-HS A antibody region.

136. The multivalent antibody of any one of claims 128-133, wherein the anti-HSA antibody region is N-terminal to one or both of the anti- PD-1 antibody region and / or the anti-CD2 antibody region.

137. The multivalent antibody of any one of claims 128-133, wherein the multivalent antibody comprises a configuration, progressing N-terminal to C-terminal, of PD1: CD2: HSA;PD1: HSA: CD2; CD2: PD1: HSA; HSA: PD1: CD2; HSA: CD2: PD1; or CD2: HSA: PD1.

138. The multivalent antibody of any one of claims 1-20, comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 897.

139. The multivalent antibody of any one of claims 1-20, comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 924.

140. The multivalent antibody of any one of claims 1-20, comprising a sequence that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 930.

141. The multivalent antibody of any one of claims 124-140, further comprising a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to SEQ ID NO: 780 and a constant region that is at least 90% identical (e.g., 95%, 99%, or 100% identical) to one of SEQ ID NO: 781 or 782.

142. A method of treating, preventing, or reducing the severity of an autoimmune disease or inflammatory disease, the method comprising contacting an effector cell with an effective amount of the multivalent antibody of any one of claims 1 to 141.

143. A method of treating, preventing, or reducing the severity of an autoimmune disease or inflammatory disease in a subject in need thereof, the method comprising contacting an effector cell with an effective amount of the multivalent antibody of any one of claims 1 to 141.

144. The method of claim 142-143, wherein the effector cell is in vitro, ex vivo, or in vivo.

145. A method of treating, preventing, or reducing the severity of an autoimmune disease or inflammatory disease in a subject, the method comprising administering to the subject an effective amount of the multivalent antibody of any one of claims 1 to 141.

146. The method of any one of claims 142-145, wherein the autoimmune diseases or inflammatory disease is Type 1 diabetes (T1D), Rheumatoid arthritis (RA), Systemic lupus062460-503001WG ery thematosus (SLE), Myasthenia gravis (\1G). Autoimmune uveitis (AU), Sjogren's syndrome (SjS), Inflammatory' bowel diseases (IBD), or Autoimmune hepatitis (AIH), Behcet's disease (BD).

147. A method of treating, preventing, or reducing the severity of a graft-versus-host disease (GVHD), the method comprising contacting an effector cell with an effective amount of the multivalent antibody of any one of claims 1 to 141.

148. A method of treating, preventing, or reducing the severity of a graft-versus-host disease (GVHD) in a subj ect in need thereof, the method comprising contacting an effector cell with an effective amount of the multivalent antibody of any one of claims 1 to 141.

149. The method of claims 147-148, wherein the effector cell is in vitro, ex vivo, or in vivo.

150. A method of treating, preventing, or reducing the severity of a graft-versus-host disease (GVHD) in a subject, the method comprising administering to the subject an effective amount of the multivalent antibody of any one of claims 1 to 141.

151. The method of claims 142-150, further comprising administering to the subject an effective amount of an immunomodulatory drug.

152. The method of claim 151, wherein the immunomodulatory' drug is a checkpoint inhibitor, adoptive T cell therapy, monoclonal antibody therapy, corticosteroid, tumor necrosis factor inhibitor, interleukin- 1 (IL-1) inhibitor, interleukin-6 (IL-6) inhibitor, T cell inhibitor, B-cell inhibitor, or Janus Kinase inhibitor.

153. The method of claims 151-152, wherein the immunomodulatory7drug is an immunosuppressant.

154. The method of any one of claims 151-153, further comprising administering an effective amount of a standard of care therapy.

155. A pharmaceutical composition comprising the multivalent antibody of any one of claims 1 to 141 and a pharmaceutically7acceptable carrier, diluent, or excipient.

156. The pharmaceutical composition of claim 155, for use as a medicament in the treatment of an autoimmune disease or inflammatory disease or in the treatment of a graft-versus-host disease (GVHD).

157. A pharmaceutical composition comprising the multivalent antibody of any one of claims 1 to 141 and an effective amount of an anti-PD-1 antibody, and a pharmaceutically acceptable carrier, diluent, or excipient.

158. The pharmaceutical composition of claim 157. wherein the anti-PD-1 antibody is rosnilimab and peresolimab.062460-503001WG 159. A method of treating, preventing, or reducing the severity of an autoimmune disease or inflammatory disease in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 155-158.

160. The method of claim 159, wherein the autoimmune diseases or inflammatory disease is Type 1 diabetes (T1D), Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Myasthenia gravis (MG), Autoimmune uveitis (AU), Sjogren's syndrome (SjS), Inflammatory bowel diseases (IBD), or Autoimmune hepatitis (AIH), Behcet's disease (BD).

161. A method of treating, preventing, or reducing the severity of a graft-versus-host disease (GVHD) in a subject, the method comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 155-158.

162. The method of claims 159-161, further comprising administering to the subject an effective amount of an anti-PD-1 antibody.

163. The method of claim 162, wherein the pharmaceutical composition is administered before the anti-PD-1 antibody.

164. The method of claim 162, wherein the pharmaceutical composition is administered simultaneous with the anti-PD-1 antibody.

165. The method of claim 162, wherein the pharmaceutical composition is administered after the anti-PD-1 antibody.

166. The method of claims 159-161, wherein the subject has previously been treated with an anti-PD-1 antibody.

167. The method of claims 159-161, further comprising administering to the subject an effective amount of an immunomodulatory drug.

168. The method of claim 167, wherein the immunomodulatory’ drug is a checkpoint inhibitor, adoptive T cell therapy, monoclonal antibody therapy, corticosteroid, tumor necrosis factor inhibitor, interleukin-1 (IL-1) inhibitor, interleukin-6 (IL-6) inhibitor, T cell inhibitor, B-cell inhibitor, or Janus Kinase inhibitor.

169. The method of claims 167-168, wherein the immunomodulatory drug is an immunosuppressant.

170. The method of any one of claims 167-169, further comprising administering an effective amount of a standard of care therapy.

171. A polynucleotide or plurality of polynucleotides encoding the multivalent antibody of any one of claims 1 to 141.

172. A vector comprising the polynucleotide or plurality of polynucleotides of claim 171.

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