Anti-CD3 antibodies and compositions and methods related thereto

Anti-CD3 antibodies with optimized CDR sequences improve affinity and specificity, overcoming developmental and clinical use challenges, enhancing their suitability for therapeutic applications.

WO2026006458A1PCT designated stage Publication Date: 2026-01-02ADIMAB LLC
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Patent Information

Application Number
PCT/US2025/035266
Authority / Receiving Office
WO · WO
Patent Type
Applications
Current Assignee / Owner
Priority Date
2025-02-21
Filing Date
2025-06-25
Publication Date
2026-01-02

AI Technical Summary

Technical Problem

Existing anti-CD3 antibodies and antigen-binding antibody fragments face issues such as affinity, specificity, cross-reactivity, T cell activation, developability, and immunogenicity, which hinder their development and clinical use.

Method used

Development of anti-CD3 antibodies and antigen-binding antibody fragments with specific heavy chain variable domain (VH) complementarity determining regions (CDRs) sequences, including CDRH1, CDRH2, and CDRH3, optimized for improved affinity, specificity, and reduced immunogenicity.

Benefits of technology

The optimized CDR sequences enhance the performance of anti-CD3 antibodies, addressing issues of affinity, specificity, and immunogenicity, making them suitable for development and clinical use.

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Abstract

The present disclosure includes anti-CD3 binding domains such as VHHs and antibodies and / or antigen-binding fragments including such domains. Also included are multi-specific antibodies and antibody fragments. The present disclosure further includes nucleic acids encoding such antibodies or antibody fragments, vectors containing such nucleic acids, and host cells comprising such nucleic acids and / or vectors. Further included are pharmaceutical compositions and methods relating to anti-CD3 antibodies or antigen-binding fragments.
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Description

[0001] Attorney Docket No.: 1160430.004613 ANTI-CD3 ANTIBODIES AND COMPOSITIONS AND METHODS RELATED THERETO CROSS-REFERENCE TO RELATED APPLICATIONS [1] This application claims priority to: U.S. Provisional Application No.63 / 663,985, filed on June 25, 2024, entitled “ANTI-CD3 ANTIBODIES AND COMPOSITIONS AND METHODS RELATED THERETO”; U.S. Provisional Application No.63 / 701,112, filed on September 30, 2024, entitled “ANTI-CD3 ANTIBODIES AND COMPOSITIONS AND METHODS RELATED THERETO”; and U.S. Provisional Application No.63 / 761,391, filed on February 21, 2025, entitled “ANTI-CD3 ANTIBODIES AND COMPOSITIONS AND METHODS RELATED THERETO.” The contents of said applications are incorporated by reference in their entirety herein. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [2] The contents of the electronic sequence listing (1160430_004613_SL.xml; Size: 4,416,954 bytes; and Date of Creation: June 17, 2025) is herein incorporated by reference in its entirety. BACKGROUND [3] Cell proliferative disorders, such as cancer, are characterized by the uncontrolled growth of cell subpopulations. They are the leading cause of death in the developed world and the second leading cause of death in developing countries, with a total number of new cancer cases per year expected to rise to 23.6 million by 2030. The National Cancer Institute estimates that almost 2 million new cases of cancer will be diagnosed in the U.S. and greater than 600,000 Americans will die of cancer in 2018. Cancer care thus represents a significant and ever-increasing societal burden. [4] The idea of using the cytotoxic capacity of T cells to kill tumor cells through use of CD3 targeting bispecific antibodies dates back to the mid-1980s. (Staerz et al. Nature 1985314: 628-32). Many bispecific antibodies developed to date contain a first binding site specific to CD3 for T-cell recruitment and activation, and a second binding site for a targeted disease-associated antigen, such as an antigen produced by a 1 Attorney Docket No.: 1160430.004613 tumor cell. CD3 bispecific antibodies trigger the CD3 surface receptor on T cells by binding to their second target protein expressed on tumors such that available T cells can bind to target-expressing cells via bridging by the CD3 bispecific antibody, irrespective of the peptide / MHC specificity of their T-cell receptor. (See, e.g., Bassan, 2012, Blood 120:5094-95). Bridging of T cells and tumor cells using CD3 bispecific antibodies can induce dramatic regression of advanced-stage malignancies and, in some cases, lead to complete remission. Currently, more than 25 different CD3 bispecific antibodies are in clinical development for treatment of hematologic malignancies or solid cancers by targeting CD19, CD20, CD33, and CD123, or EpCAM, HER2, PSMA, and CEA, respectively. (See, e.g., Liu et al. Front Immunol 20178:38). [5] The species camelid, which includes but is not limited to camels, dromedaries, and llamas, is known to naturally express HCAb antibodies, which include the smallest known naturally-occurring VHH binding domain (Hamers-Casterman et al., Nature.1993). Without light chains and CH1 regions, camelid and synthetically-derived HCAbs have reduced molecular weight relative to conventional antibodies (such as human IgGs), approximately 90 kDa versus about 150 kD for conventional antibodies (Spinelli et al., Nat Structural Biol. 1996). [6] Some anti-CD3 VHH or HCAb antibodies are known in the art, including monospecific and bispecific antibody formats. However, these antibodies typically possess issues such as those related to affinity, specificity, cross-reactivity, T cell activation, developability, tendency to degrade, immunogenicity, etc. Accordingly, there is an unmet need for the provision of anti-CD3 VHH domains and related constructs with properties suited for development and / or clinical use. SUMMARY [7] One aspect of the present disclosure provides anti-CD3 antibodies and antigen- binding antibody fragments, e.g., those derived from camelid antibodies. The anti-CD3 antibodies and antigen-binding antibody fragments may comprise a first heavy chain variable domain (VH-1) comprising: (a) a first heavy chain complementarity determining region (CDR) 1 (CDRH1-1); (b) a first heavy chain CDR2 (CDRH2-1); and (c) a first heavy chain CDR3 (CDRH3-1), wherein (a) the amino acid sequence of the CDRH1-1 comprises or consists of: a CDR1 amino acid sequence contained in any one of the variable heavy domain 2 Attorney Docket No.: 1160430.004613 of heavy chain (VHH) amino acid sequences listed in Table 13A, 1A, or 24A; and / or any one of the CDR1 amino acid sequences listed in Table 13B, 1B, or 24B; (b) the amino acid sequence of the CDRH2-1 comprises or consists of: a CDR2 amino acid sequence contained in any one of the VHH amino acid sequences listed in Table 13A, 1A, or 24A; and / or any one of the CDR2 amino acid sequences listed in Table 13B, 1B, or 24B; and (c) the amino acid sequence of the CDRH3-1 comprises or consists of: a CDRH3 amino acid sequence contained in any one of the VHH amino acid sequences listed in Table 13A, 1A, or 24A; and / or any one of the CDR3 amino acid sequences listed in Table 13B, 1B, or 24B. Preferably, each of the CDRs is that of the same anti-CD3 antibody, which may optionally be selected from (1) Antibody Nos.21-h1 through 21-h44, 4-h1 through 4-h34, 14-h1 through 14-h48, 15-h1 through 15-h29, 19-h1 through 19-h32, and 25-h1 through 25-h28, (2) Antibody Nos.1 through 30, or (3) Antibody Nos.31-48, 22, and 27. [8] In some embodiments, the anti-CD3 antibodies and antigen-binding antibody fragments may comprise any of the consensus CDR sequences or a set of consensus CDR1, 2, and 3 sequences disclosed in Table 13B or 1B. [9] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 of the anti-CD3 antibody or antigen-binding antibody fragment may comprise or consist of (I) (1) (i) SEQ ID NO: 9412, 9414, and 9416, respectively; (ii) SEQ ID NO: 9422, 9424, and 9426, respectively; or (iii) SEQ ID NO: 9432, 9434, and 9436, respectively; (2) (i) SEQ ID NO: 9512, 9514, and 9516, respectively; (ii) SEQ ID NO: 9522, 9524, and 9526, respectively; or (iii) SEQ ID NO: 9532, 9534, and 9536, respectively; (3) (i) SEQ ID NO: 9612, 9614, and 9616, respectively; (ii) SEQ ID NO: 9622, 9624, and 9626, respectively; or (iii) SEQ ID NO: 9632, 9634, and 9636, respectively; (4) (i) SEQ ID NO: 9712, 9714, and 9716, respectively; (ii) SEQ ID NO: 9722, 9724, and 9726, respectively; or (iii) SEQ ID NO: 9732, 9734, and 9736, respectively; (5) (i) SEQ ID NO: 9812, 9814, and 9816, respectively; (ii) SEQ ID NO: 9822, 9824, and 9826, respectively; or (iii) SEQ ID NO: 9832, 9834, and 9836, respectively; (6) (i) SEQ ID NO: 9912, 9914, and 9916, respectively; (ii) SEQ ID NO: 9922, 9924, and 9926, respectively; (iii) SEQ ID NO: 9932, 9934, and 9936, respectively; or (iv) SEQ ID NO: 9942, 9944, and 9946, respectively; or (II) (1) SEQ ID NO: 3112, 3114, and 3116, respectively; (2) SEQ ID NO: 3212, 3214, and 3216, respectively; or (3) SEQ ID NO: 3312, 3314, and 3316, respectively.

[0010] In some embodiments, the three CDR sequences may be of or from a single anti-CD3 antibody listed in Table 13A, 13B, 1A, 1B, 24A, or 24B. 3 Attorney Docket No.: 1160430.004613

[0011] In some embodiments, the three CDR sequences may be of or from two or three different anti-CD3 antibodies listed in Table 13A, 13B, 1A, 1B, 24A, or 24B which share the same Bin code as shown in Table 4. In certain embodiments, the three CDR sequences may be of or from two or three different anti-CD3 antibodies listed in Table 13A, 13B, 1A, 1B, 24A, or 24B which have the Bin code “2” as shown in Table 4. In certain cases, the three CDR sequences may be of or from two or three different anti-CD3 antibodies listed in Table 13A, 13B, 1A, 1B, 24A, or 24B which have the Bin code “Other” as shown in Table 4.

[0012] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 of the anti-CD3 antibody or antigen-binding antibody fragment may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in the VHH amino acid sequence of a first anti-CD3 antibody listed in Table 13A, 1A, or 24A. In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 of the anti-CD3 antibody or antigen-binding antibody fragment may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences, respectively, of a first anti- CD3 antibody listed in Table 13B, 1B or 24B.

[0013] In certain embodiments, the first anti-CD3 antibody may be or the CDRH1-1, the CDRH2-1, and the CDRH3-1 may be the CDR1, 2, and 3 of: Antibody No.21-h14 or an anti- CD3 antibody selected from (i-1) Antibody No.21-h1; (i-2) Antibody No.21-h2; (i-3) Antibody No.21-h3; (i-4) Antibody No.21-h4; (i-5) Antibody No.21-h5; (i-6) Antibody No. 21-h6; (i-7) Antibody No.21-h7; (i-8) Antibody No.21-h8; (i-9) Antibody No.21-h9; (i-10) Antibody No.21-h10; (i-11) Antibody No.21-h11; (i-12) Antibody No.21-h12; (i-13) Antibody No.21-h13; (i-14) Antibody No.21-h14; (i-15) Antibody No.21-h15; (i-16) Antibody No.21-h16; (i-17) Antibody No.21-h17; (i-18) Antibody No.21-h18; (i-19) Antibody No.21-h19; (i-20) Antibody No.21-h20; (i-21) Antibody No.21-h21; (i-22) Antibody No.21-h22; (i-23) Antibody No.21-h23; (i-24) Antibody No.21-h24; (i-25) Antibody No.21-h25; (i-26) Antibody No.21-h26; (i-27) Antibody No.21-h27; (i-28) Antibody No.21-h28; (i-29) Antibody No.21-h29; (i-30) Antibody No.21-h30; (i-31) Antibody No.21-h31; (i-32) Antibody No.21-h32; (i-33) Antibody No.21-h33; (i-34) Antibody No.21-h34; (i-35) Antibody No.21-h35; (i-36) Antibody No.21-h36; (i-37) Antibody No.21-h37; (i-38) Antibody No.21-h38; (i-39) Antibody No.21-h39; (i-40) Antibody No.21-h40; (i-41) Antibody No.21-h41; (i-42) Antibody No.21-h42; (i-43) Antibody No.21-h43; or (i-44) Antibody No.21-h44. 4 Attorney Docket No.: 1160430.004613

[0014] In certain embodiments, the first anti-CD3 antibody may be or the CDRH1-1, the CDRH2-1, and the CDRH3-1 may be the CDR1, 2, and 3 of: Antibody No.4-h1, Antibody No.4-h10, or Antibody No.4-h19, or an anti-CD3 antibody selected from (ii-1) Antibody No.4-h1; (ii-2) Antibody No.4-h2; (ii-3) Antibody No.4-h3; (ii-4) Antibody No.4-h4; (ii-5) Antibody No.4-h5; (ii-6) Antibody No.4-h6; (ii-7) Antibody No.4-h7; (ii-8) Antibody No. 4-h8; (ii-9) Antibody No.4-h9; (ii-10) Antibody No.4-h10; (ii-11) Antibody No.4-h11; (ii- 12) Antibody No.4-h12; (ii-13) Antibody No.4-h13; (ii-14) Antibody No.4-h14; (ii-15) Antibody No.4-h15; (ii-16) Antibody No.4-h16; (ii-17) Antibody No.4-h17; (ii-18) Antibody No.4-h18; (ii-19) Antibody No.4-h19; (ii-20) Antibody No.4-h20; (ii-21) Antibody No.4-h21; (ii-22) Antibody No.4-h22; (ii-23) Antibody No.4-h23; (ii-24) Antibody No.4-h24; (ii-25) Antibody No.4-h25; (ii-26) Antibody No.4-h26; (ii-27) Antibody No.4-h27; (ii-28) Antibody No.4-h28; (ii-29) Antibody No.4-h29; (ii-30) Antibody No.4-h30; (ii-31) Antibody No.4-h31; (ii-32) Antibody No.4-h32; (ii-33) Antibody No.4-h33; or (ii-34) Antibody No.4-h34.

[0015] In certain embodiments, the first anti-CD3 antibody may be or the CDRH1-1, the CDRH2-1, and the CDRH3-1 may be the CDR1, 2, and 3 of: Antibody No.14-h4, Antibody No.14-h1, Antibody No.14-h19, or Antibody No.14-h27, or an anti-CD3 antibody selected from (iii-1) Antibody No.14-h1; (iii-2) Antibody No.14-h2; (iii-3) Antibody No.14-h3; (iii- 4) Antibody No.14-h4; (iii-5) Antibody No.14-h5; (iii-6) Antibody No.14-h6; (iii-7) Antibody No.14-h7; (iii-8) Antibody No.14-h8; (iii-9) Antibody No.14-h9; (iii-10) Antibody No.14-h10; (iii-11) Antibody No.14-h11; (iii-12) Antibody No.14-h12; (iii-13) Antibody No.14-h13; (iii-14) Antibody No.14-h14; (iii-15) Antibody No.14-h15; (iii-16) Antibody No.14-h16; (iii-17) Antibody No.14-h17; (iii-18) Antibody No.14-h18; (iii-19) Antibody No.14-h19; (iii-20) Antibody No.14-h20; (iii-21) Antibody No.14-h21; (iii-22) Antibody No.14-h22; (iii-23) Antibody No.14-h23; (iii-24) Antibody No.14-h24; (iii-25) Antibody No.14-h25; (iii-26) Antibody No.14-h26; (iii-27) Antibody No.14-h27; (iii-28) Antibody No.14-h28; (iii-29) Antibody No.14-h29; (iii-30) Antibody No.14-h30; (iii-31) Antibody No.14-h31; (iii-32) Antibody No.14-h32; (iii-33) Antibody No.14-h33; (iii-34) Antibody No.14-h34; (iii-35) Antibody No.14-h35; (iii-36) Antibody No.14-h36; (iii-37) Antibody No.14-h37; (iii-38) Antibody No.14-h38; (iii-39) Antibody No.14-h39; (iii-40) Antibody No.14-h40; (iii-41) Antibody No.14-h41; (iii-42) Antibody No.14-h42; (iii-43) Antibody No.14-h43; (iii-44) Antibody No.14-h44; (iii-45) Antibody No.14-h45; (iii-46) Antibody No.14-h46; (iii-47) Antibody No.14-h47; or (iii-48) Antibody No.14-h48. 5 Attorney Docket No.: 1160430.004613

[0016] In certain embodiments, the first anti-CD3 antibody may be or the CDRH1-1, the CDRH2-1, and the CDRH3-1 may be the CDR1, 2, and 3 of: Antibody No.15-h1, Antibody No.15-h6, Antibody No.15-h13, or Antibody No.15-h16, or an anti-CD3 antibody selected from (iv-1) Antibody No.15-h1; (iv-2) Antibody No.15-h2; (iv-3) Antibody No.15-h3; (iv- 4) Antibody No.15-h4; (iv-5) Antibody No.15-h5; (iv-6) Antibody No.15-h6; (iv-7) Antibody No.15-h7; (iv-8) Antibody No.15-h8; (iv-9) Antibody No.15-h9; (iv-10) Antibody No.15-h10; (iv-11) Antibody No.15-h11; (iv-12) Antibody No.15-h12; (iv-13) Antibody No.15-h13; (iv-14) Antibody No.15-h14; (iv-15) Antibody No.15-h15; (iv-16) Antibody No.15-h16; (iv-17) Antibody No.15-h17; (iv-18) Antibody No.15-h18; (iv-19) Antibody No.15-h19; (iv-20) Antibody No.15-h20; (iv-21) Antibody No.15-h21; (iv-22) Antibody No.15-h22; (iv-23) Antibody No.15-h23; (iv-24) Antibody No.15-h24; (iv-25) Antibody No.15-h25; (iv-26) Antibody No.15-h26; (iv-27) Antibody No.15-h27; (iv-28) Antibody No.15-h28; or (iv-29) Antibody No.15-h29.

[0017] In certain embodiments, the first anti-CD3 antibody may be or the CDRH1-1, the CDRH2-1, and the CDRH3-1 may be the CDR1, 2, and 3 of: Antibody No.19-h3 or Antibody No.19-h29, or an anti-CD3 antibody selected from (v-1) Antibody No.19-h1; (v-2) Antibody No.19-h2; (v-3) Antibody No.19-h3; (v-4) Antibody No.19-h4; (v-5) Antibody No.19-h5; (v-6) Antibody No.19-h6; (v-7) Antibody No.19-h7; (v-8) Antibody No.19-h8; (v-9) Antibody No.19-h9; (v-10) Antibody No.19-h10; (v-11) Antibody No.19-h11; (v-12) Antibody No.19-h12; (v-13) Antibody No.19-h13; (v-14) Antibody No.19-h14; (v-15) Antibody No.19-h15; (v-16) Antibody No.19-h16; (v-17) Antibody No.19-h17; (v-18) Antibody No.19-h18; (v-19) Antibody No.19-h19; (v-20) Antibody No.19-h20; (v-21) Antibody No.19-h21; (v-22) Antibody No.19-h22; (v-23) Antibody No.19-h23; (v-24) Antibody No.19-h24; (v-25) Antibody No.19-h25; (v-26) Antibody No.19-h26; (v-27) Antibody No.19-h27; (v-28) Antibody No.19-h28; (v-29) Antibody No.19-h29; (v-30) Antibody No.19-h30; (v-31) Antibody No.19-h31; or (v-32) Antibody No.19-h32.

[0018] In certain embodiments, the first anti-CD3 antibody may be or the CDRH1-1, the CDRH2-1, and the CDRH3-1 may be the CDR1, 2, and 3 of: Antibody No.25-h3 or Antibody No.25-h12, or an anti-CD3 antibody selected from (vi-1) Antibody No.25-h1; (vi- 2) Antibody No.25-h2; (vi-3) Antibody No.25-h3; (vi-4) Antibody No.25-h4; (vi-5) Antibody No.25-h5; (vi-6) Antibody No.25-h6; (vi-7) Antibody No.25-h7; (vi-8) Antibody No.25-h8; (vi-9) Antibody No.25-h9; (vi-10) Antibody No.25-h10; (vi-11) Antibody No. 25-h11; (vi-12) Antibody No.25-h12; (vi-13) Antibody No.25-h13; (vi-14) Antibody No. 6 Attorney Docket No.: 1160430.004613 25-h14; (vi-15) Antibody No.25-h15; (vi-16) Antibody No.25-h16; (vi-17) Antibody No. 25-h17; (vi-18) Antibody No.25-h18; (vi-19) Antibody No.25-h19; (vi-20) Antibody No. 25-h20; (vi-21) Antibody No.25-h21; (vi-22) Antibody No.25-h22; (vi-23) Antibody No. 25-h23; (vi-24) Antibody No.25-h24; (vi-25) Antibody No.25-h25; (vi-26) Antibody No. 25-h26; (vi-27) Antibody No.25-h27; or (vi-28) Antibody No.25-h28.

[0019] In certain embodiments, the first anti-CD3 antibody may be or the CDRH1-1, the CDRH2-1, and the CDRH3-1 may be the CDR1, 2, and 3 of: Antibody No.21, 4, 14, 15, 19, or 25, or an anti-CD3 antibody selected from (i) Antibody No.1; (ii) Antibody No.2; (iii) Antibody No.3; (iv) Antibody No.4; (v) Antibody No.5; (vi) Antibody No.6; (vii) Antibody No.7; (viii) Antibody No.8; (ix) Antibody No.9; (x) Antibody No.10; (xi) Antibody No.11; (xii) Antibody No.12; (xiii) Antibody No.13; (xiv) Antibody No.14; (xv) Antibody No.15; (xvi) Antibody No.16; (xvii) Antibody No.17; (xviii) Antibody No.18; (xix) Antibody No.19; (xx) Antibody No.20; (xxi) Antibody No.21; (xxii) Antibody No. 22; (xxiii) Antibody No.23; (xxiv) Antibody No.24; (xv) Antibody No.25; (xvi) Antibody No.26; (xvii) Antibody No.27; (xviii) Antibody No.28; (xix) Antibody No.29; or (xxx) Antibody No.30.

[0020] In certain embodiments, the first anti-CD3 antibody may be or the CDRH1-1, the CDRH2-1, and the CDRH3-1 may be the CDR1, 2, and 3 of: (xxxi) Antibody No.31; (xxxii) Antibody No.32; (xxxiii) Antibody No.33; (xxxiv) Antibody No.34; (xxxv) Antibody No. 35; (xxxvi) Antibody No.36; (xxxvii) Antibody No.37; (xxxviii) Antibody No.38; (xxxix) Antibody No.39; (xl) Antibody No.40; (xli) Antibody No.41; (xlii) Antibody No.42; (xliii) Antibody No.43; (xliv) Antibody No.44; (xlv) Antibody No.45; (xlvi) Antibody No.46; (xlvii) Antibody No.47; or (xlviii) Antibody No.48.

[0021] In certain embodiments, the amino acid sequence of the VH-1 may comprise or consist of: (a) the VHH amino acid sequence of the anti-CD3 antibody listed in Table 13A, 1A, or 24A; or (b) a variant thereof having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to said VHH amino acid sequence.

[0022] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in the VHH amino acid sequence of: SEQ ID NO: 4140 or any of (i-1) SEQ ID NO: 4010; (i-2) SEQ ID NO: 4020; (i-3) SEQ ID NO: 4030; (i-4) SEQ ID NO: 4040; (i-5) SEQ ID NO: 4050; (i-6) SEQ ID NO: 4060; (i-7) SEQ ID NO: 4070; (i-8) 7 Attorney Docket No.: 1160430.004613 SEQ ID NO: 4080; (i-9) SEQ ID NO: 4090; (i-10) SEQ ID NO: 4100; (i-11) SEQ ID NO: 4110; (i-12) SEQ ID NO: 4120; (i-13) SEQ ID NO: 4130; (i-14) SEQ ID NO: 4140; (i-15) SEQ ID NO: 4150; (i-16) SEQ ID NO: 4160; (i-17) SEQ ID NO: 4170; (i-18) SEQ ID NO: 4180; (i-19) SEQ ID NO: 4190; (i-20) SEQ ID NO: 4200; (i-21) SEQ ID NO: 4210; (i-22) SEQ ID NO: 4220; (i-23) SEQ ID NO: 4230; (i-24) SEQ ID NO: 4240; (i-25) SEQ ID NO: 4250; (i-26) SEQ ID NO: 4260; (i-27) SEQ ID NO: 4270; (i-28) SEQ ID NO: 4280; (i-29) SEQ ID NO: 4290; (i-30) SEQ ID NO: 4300; (i-31) SEQ ID NO: 4310; (i-32) SEQ ID NO: 4320; (i-33) SEQ ID NO: 4330; (i-34) SEQ ID NO: 4340; (i-35) SEQ ID NO: 4350; (i-36) SEQ ID NO: 4360; (i-37) SEQ ID NO: 4370; (i-38) SEQ ID NO: 4380; (i-39) SEQ ID NO: 4390; (i-40) SEQ ID NO: 4400; (i-41) SEQ ID NO: 4410; (i-42) SEQ ID NO: 4420; (i-43) SEQ ID NO: 4430; or (i-44) SEQ ID NO: 4440.

[0023] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in the VHH amino acid sequence of: SEQ ID NO: 5010, 5100, or 5190, or any of (ii-1) SEQ ID NO: 5010; (ii-2) SEQ ID NO: 5020; (ii-3) SEQ ID NO: 5030; (ii-4) SEQ ID NO: 5040; (ii-5) SEQ ID NO: 5050; (ii-6) SEQ ID NO: 5060; (ii-7) SEQ ID NO: 5070; (ii-8) SEQ ID NO: 5080; (ii-9) SEQ ID NO: 5090; (ii-10) SEQ ID NO: 5100; (ii-11) SEQ ID NO: 5110; (ii-12) SEQ ID NO: 5120; (ii-13) SEQ ID NO: 5130; (ii-14) SEQ ID NO: 5140; (ii-15) SEQ ID NO: 5150; (ii-16) SEQ ID NO: 5160; (ii-17) SEQ ID NO: 5170; (ii-18) SEQ ID NO: 5180; (ii-19) SEQ ID NO: 5190; (ii-20) SEQ ID NO: 5200; (ii-21) SEQ ID NO: 5210; (ii-22) SEQ ID NO: 5220; (ii-23) SEQ ID NO: 5230; (ii-24) SEQ ID NO: 5240; (ii-25) SEQ ID NO: 5250; (ii-26) SEQ ID NO: 5260; (ii-27) SEQ ID NO: 5270; (ii-28) SEQ ID NO: 5280; (ii-29) SEQ ID NO: 5290; (ii-30) SEQ ID NO: 5300; (ii-31) SEQ ID NO: 5310; (ii-32) SEQ ID NO: 5320; (ii-33) SEQ ID NO: 5330; or (ii-34) SEQ ID NO: 5340.

[0024] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in the VHH amino acid sequence of: SEQ ID NO: 6040, 6010, 6190, or 6270, or any of (iii-1) SEQ ID NO: 6010; (iii-2) SEQ ID NO: 6020; (iii-3) SEQ ID NO: 6030; (iii-4) SEQ ID NO: 6040; (iii-5) SEQ ID NO: 6050; (iii-6) SEQ ID NO: 6060; (iii-7) SEQ ID NO: 6070; (iii-8) SEQ ID NO: 6080; (iii-9) SEQ ID NO: 6090; (iii-10) SEQ ID NO: 6100; (iii-11) SEQ ID NO: 6110; (iii-12) SEQ ID NO: 6120; (iii-13) SEQ ID NO: 6130; (iii-14) SEQ ID NO: 6140; (iii-15) SEQ ID NO: 6150; (iii-16) SEQ ID NO: 6160; (iii-17) SEQ ID NO: 6170; (iii-18) SEQ ID NO: 6180; (iii-19) SEQ ID NO: 6190; (iii-20) 8 Attorney Docket No.: 1160430.004613 SEQ ID NO: 6200; (iii-21) SEQ ID NO: 6210; (iii-22) SEQ ID NO: 6220; (iii-23) SEQ ID NO: 6230; (iii-24) SEQ ID NO: 6240; (iii-25) SEQ ID NO: 6250; (iii-26) SEQ ID NO: 6260; (iii-27) SEQ ID NO: 6270; (iii-28) SEQ ID NO: 6280; (iii-29) SEQ ID NO: 6290; (iii-30) SEQ ID NO: 6300; (iii-31) SEQ ID NO: 6310; (iii-32) SEQ ID NO: 6320; (iii-33) SEQ ID NO: 6330; (iii-34) SEQ ID NO: 6340; (iii-35) SEQ ID NO: 6350; (iii-36) SEQ ID NO: 6360; (iii-37) SEQ ID NO: 6370; (iii-38) SEQ ID NO: 6380; (iii-39) SEQ ID NO: 6390; (iii-40) SEQ ID NO: 6400; (iii-41) SEQ ID NO: 6410; (iii-42) SEQ ID NO: 6420; (iii-43) SEQ ID NO: 6430; (iii-44) SEQ ID NO: 6440; (iii-45) SEQ ID NO: 6450; (iii-46) SEQ ID NO: 6460; (iii-47) SEQ ID NO: 6470; or (iii-48) SEQ ID NO: 6480.

[0025] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in the VHH amino acid sequence of: SEQ ID NO: 7010, 7060, 7130, or 7160, or any of (iv-1) SEQ ID NO: 7010; (iv-2) SEQ ID NO: 7020; (iv-3) SEQ ID NO: 7030; (iv-4) SEQ ID NO: 7040; (iv-5) SEQ ID NO: 7050; (iv-6) SEQ ID NO: 7060; (iv-7) SEQ ID NO: 7070; (iv-8) SEQ ID NO: 7080; (iv-9) SEQ ID NO: 7090; (iv-10) SEQ ID NO: 7100; (iv-11) SEQ ID NO: 7110; (iv-12) SEQ ID NO: 7120; (iv-13) SEQ ID NO: 7130; (iv-14) SEQ ID NO: 7140; (iv-15) SEQ ID NO: 7150; (iv-16) SEQ ID NO: 7160; (iv-17) SEQ ID NO: 7170; (iv-18) SEQ ID NO: 7180; (iv-19) SEQ ID NO: 7190; (iv-20) SEQ ID NO: 7200; (iv-21) SEQ ID NO: 7210; (iv-22) SEQ ID NO: 7220; (iv-23) SEQ ID NO: 7230; (iv-24) SEQ ID NO: 7240; (iv-25) SEQ ID NO: 7250; (iv-26) SEQ ID NO: 7260; (iv-27) SEQ ID NO: 7270; (iv-28) SEQ ID NO: 7280; or (iv-29) SEQ ID NO: 7290.

[0026] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in the VHH amino acid sequence of: SEQ ID NO: 8030 or 8290, or any of (v-1) SEQ ID NO: 8010; (v-2) SEQ ID NO: 8020; (v-3) SEQ ID NO: 8030; (v-4) SEQ ID NO: 8040; (v-5) SEQ ID NO: 8050; (v-6) SEQ ID NO: 8060; (v-7) SEQ ID NO: 8070; (v-8) SEQ ID NO: 8080; (v-9) SEQ ID NO: 8090; (v-10) SEQ ID NO: 8100; (v- 11) SEQ ID NO: 8110; (v-12) SEQ ID NO: 8120; (v-13) SEQ ID NO: 8130; (v-14) SEQ ID NO: 8140; (v-15) SEQ ID NO: 8150; (v-16) SEQ ID NO: 8160; (v-17) SEQ ID NO: 8170; (v-18) SEQ ID NO: 8180; (v-19) SEQ ID NO: 8190; (v-20) SEQ ID NO: 8200; (v-21) SEQ ID NO: 8210; (v-22) SEQ ID NO: 8220; (v-23) SEQ ID NO: 8230; (v-24) SEQ ID NO: 8240; (v-25) SEQ ID NO: 8250; (v-26) SEQ ID NO: 8260; (v-27) SEQ ID NO: 8270; (v-28) 9 Attorney Docket No.: 1160430.004613 SEQ ID NO: 8280; (v-29) SEQ ID NO: 8290; (v-30) SEQ ID NO: 8300; (v-31) SEQ ID NO: 8310; or (v-32) SEQ ID NO: 8320.

[0027] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in the VHH amino acid sequence of: SEQ ID NO: 9030 or 9120, or any of (vi-1) SEQ ID NO: 9010; (vi-2) SEQ ID NO: 9020; (vi-3) SEQ ID NO: 9030; (vi-4) SEQ ID NO: 9040; (vi-5) SEQ ID NO: 9050; (vi-6) SEQ ID NO: 9060; (vi-7) SEQ ID NO: 9070; (vi-8) SEQ ID NO: 9080; (vi-9) SEQ ID NO: 9090; (vi-10) SEQ ID NO: 9100; (vi-11) SEQ ID NO: 9110; (vi-12) SEQ ID NO: 9120; (vi-13) SEQ ID NO: 9130; (vi-14) SEQ ID NO: 9140; (vi-15) SEQ ID NO: 9150; (vi-16) SEQ ID NO: 9160; (vi-17) SEQ ID NO: 9170; (vi-18) SEQ ID NO: 9180; (vi-19) SEQ ID NO: 9190; (vi-20) SEQ ID NO: 9200; (vi-21) SEQ ID NO: 9210; (vi-22) SEQ ID NO: 9220; (vi-23) SEQ ID NO: 9230; (vi-24) SEQ ID NO: 9240; (vi-25) SEQ ID NO: 9250; (vi-26) SEQ ID NO: 9260; (vi-27) SEQ ID NO: 9270; or (vi-28) SEQ ID NO: 9280.

[0028] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (i) SEQ ID NOS: 110; (ii) SEQ ID NO: 210; (iii) SEQ ID NO: 310; (iv) SEQ ID NO: 410; (v) SEQ ID NO: 510; (vi) SEQ ID NO: 610; (vii) SEQ ID NO: 710; (viii) SEQ ID NO: 810; (ix) SEQ ID NO: 910; (x) SEQ ID NO: 1010; (xi) SEQ ID NO: 1110; (xii) SEQ ID NO: 1210; (xiii) SEQ ID NO: 1310; (xiv) SEQ ID NO: 1410; (xv) SEQ ID NO: 1510; (xvi) SEQ ID NO: 1610; (xvii) SEQ ID NO: 1710; (xviii) SEQ ID NO: 1810; (xix) SEQ ID NO: 1910; (xx) SEQ ID NO: 2010; (xxi) SEQ ID NO: 2110; (xxii) SEQ ID NO: 2210; (xxiii) SEQ ID NO: 2310; (xxiv) SEQ ID NO: 2410; (xxv) SEQ ID NO: 2510; (xxvi) SEQ ID NO: 2610; (xxvii) SEQ ID NO: 2710; (xxviii) SEQ ID NO: 2810; (xxix) SEQ ID NO: 2910; or (xxx) SEQ ID NO: 3010.

[0029] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (xxxi) SEQ ID NOS: 10110; (xxxii) SEQ ID NO: 10210; (xxxiii) SEQ ID NO: 10310; (xxxiv) SEQ ID NO: 10410; (xxxv) SEQ ID NO: 10510; (xxxvi) SEQ ID NO: 10610; (xxxvii) SEQ ID NO: 10710; (xxxviii) SEQ ID NO: 10810; (xxxix) SEQ ID NO: 10910; (xl) SEQ ID NO: 11010; (xli) SEQ ID NO: 11110; (xlii) SEQ ID NO: 11210; (xliii) SEQ ID NO: 11310; (xliv) SEQ ID 10 Attorney Docket No.: 1160430.004613 NO: 11410; (xlv) SEQ ID NO: 11510; (xlvi) SEQ ID NO: 11610; (xlvii) SEQ ID NO: 11710; or (xlviii) SEQ ID NO: 11810.

[0030] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences of: SEQ ID NOS: 4142, 4144, and 4146, respectively, or any of (i-1) SEQ ID NOS: 4012, 4014, and 4016, respectively; (i-2) SEQ ID NOS: 4022, 4024, and 4026, respectively; (i-3) SEQ ID NOS: 4032, 4034, and 4036, respectively; (i-4) SEQ ID NOS: 4042, 4044, and 4046, respectively; (i-5) SEQ ID NOS: 4052, 4054, and 4056, respectively; (i-6) SEQ ID NOS: 4062, 4064, and 4066, respectively; (i-7) SEQ ID NOS: 4072, 4074, and 4076, respectively; (i-8) SEQ ID NOS: 4082, 4084, and 4086, respectively; (i-9) SEQ ID NOS: 4092, 4094, and 4096, respectively; (i-10) SEQ ID NOS: 4102, 4104, and 4106, respectively; (i-11) SEQ ID NOS: 4112, 4114, and 4116, respectively; (i-12) SEQ ID NOS: 4122, 4124, and 4126, respectively; (i-13) SEQ ID NOS: 4132, 4134, and 4136, respectively; (i-14) SEQ ID NOS: 4142, 4144, and 4146, respectively; (i-15) SEQ ID NOS: 4152, 4154, and 4156, respectively; (i-16) SEQ ID NOS: 4162, 4164, and 4166, respectively; (i-17) SEQ ID NOS: 4172, 4174, and 4176, respectively; (i-18) SEQ ID NOS: 4182, 4184, and 4186, respectively; (i-19) SEQ ID NOS: 4192, 4194, and 4196, respectively; (i-20) SEQ ID NOS: 4202, 4204, and 4206, respectively; (i-21) SEQ ID NOS: 4212, 4214, and 4216, respectively; (i-22) SEQ ID NOS: 4222, 4224, and 4226, respectively; (i-23) SEQ ID NOS: 4232, 4234, and 4236, respectively; (i-24) SEQ ID NOS: 4242, 4244, and 4246, respectively; (i-25) SEQ ID NOS: 4252, 4254, and 4256, respectively; (i-26) SEQ ID NOS: 4262, 4264, and 4266, respectively; (i-27) SEQ ID NOS: 4272, 4274, and 4276, respectively; (i-28) SEQ ID NOS: 4282, 4284, and 4286, respectively; (i-29) SEQ ID NOS: 4292, 4294, and 4296, respectively; (i-30) SEQ ID NOS: 4302, 4304, and 4306, respectively; (i-31) SEQ ID NOS: 4312, 4314, and 4316, respectively; (i-32) SEQ ID NOS: 4322, 4324, and 4326, respectively; (i-33) SEQ ID NOS: 4332, 4334, and 4336, respectively; (i-34) SEQ ID NOS: 4342, 4344, and 4346, respectively; (i-35) SEQ ID NOS: 4352, 4354, and 4356, respectively; (i-36) SEQ ID NOS: 4362, 4364, and 4366, respectively; (i-37) SEQ ID NOS: 4372, 4374, and 4376, respectively; (i-38) SEQ ID NOS: 4382, 4384, and 4386, respectively; (i-39) SEQ ID NOS: 4392, 4394, and 4396, respectively; (i-40) SEQ ID NOS: 4402, 4404, and 4406, respectively; (i-41) SEQ ID NOS: 4412, 4414, and 4416, respectively; (i-42) SEQ ID NOS: 4422, 4424, and 4426, respectively; (i-43) SEQ ID NOS: 4432, 4434, and 4436, respectively; or (i-44) SEQ ID NOS: 4442, 4444, and 4446, respectively. 11 Attorney Docket No.: 1160430.004613

[0031] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences of: SEQ ID NOS: 5012, 5014, and 5016, respectively, SEQ ID NOS: 5102, 5104, and 5106, respectively, or SEQ ID NOS: 5192, 5194, and 5196, respectively, or any of (ii-1) SEQ ID NOS: 5012, 5014, and 5016, respectively; (ii-2) SEQ ID NOS: 5022, 5024, and 5026, respectively; (ii-3) SEQ ID NOS: 5032, 5034, and 5036, respectively; (ii-4) SEQ ID NOS: 5042, 5044, and 5046, respectively; (ii-5) SEQ ID NOS: 5052, 5054, and 5056, respectively; (ii-6) SEQ ID NOS: 5062, 5064, and 5066, respectively; (ii-7) SEQ ID NOS: 5072, 5074, and 5076, respectively; (ii-8) SEQ ID NOS: 5082, 5084, and 5086, respectively; (ii-9) SEQ ID NOS: 5092, 5094, and 5096, respectively; (ii-10) SEQ ID NOS: 5102, 5104, and 5106, respectively; (ii-11) SEQ ID NOS: 5112, 5114, and 5116, respectively; (ii-12) SEQ ID NOS: 5122, 5124, and 5126, respectively; (ii-13) SEQ ID NOS: 5132, 5134, and 5136, respectively; (ii-14) SEQ ID NOS: 5142, 5144, and 5146, respectively; (ii-15) SEQ ID NOS: 5152, 5154, and 5156, respectively; (ii-16) SEQ ID NOS: 5162, 5164, and 5166, respectively; (ii-17) SEQ ID NOS: 5172, 5174, and 5176, respectively; (ii-18) SEQ ID NOS: 5182, 5184, and 5186, respectively; (ii-19) SEQ ID NOS: 5192, 5194, and 5196, respectively; (ii-20) SEQ ID NOS: 5202, 5204, and 5206, respectively; (ii-21) SEQ ID NOS: 5212, 5214, and 5216, respectively; (ii-22) SEQ ID NOS: 5222, 5224, and 5226, respectively; (ii-23) SEQ ID NOS: 5232, 5234, and 5236, respectively; (ii-24) SEQ ID NOS: 5242, 5244, and 5246, respectively; (ii-25) SEQ ID NOS: 5252, 5254, and 5256, respectively; (ii-26) SEQ ID NOS: 5262, 5264, and 5266, respectively; (ii-27) SEQ ID NOS: 5272, 5274, and 5276, respectively; (ii-28) SEQ ID NOS: 5282, 5284, and 5286, respectively; (ii-29) SEQ ID NOS: 5292, 5294, and 5296, respectively; (ii-30) SEQ ID NOS: 5302, 5304, and 5306, respectively; (ii-31) SEQ ID NOS: 5312, 5314, and 5316, respectively; (ii-32) SEQ ID NOS: 5322, 5324, and 5326, respectively; (ii-33) SEQ ID NOS: 5332, 5334, and 5336, respectively; or (ii-34) SEQ ID NOS: 5342, 5344, and 5346, respectively.

[0032] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences of: SEQ ID NOS: 6042, 6044, and 6046, respectively, SEQ ID NOS: 6012, 6014, and 6016, respectively, SEQ ID NOS: 6192, 6194, and 6196, respectively, or SEQ ID NOS: 6272, 6274, and 6276, respectively, or any of (iii-1) SEQ ID NOS: 6012, 6014, and 6016, respectively; (iii-2) SEQ ID NOS: 6022, 6024, and 6026, respectively; (iii-3) SEQ ID NOS: 12 Attorney Docket No.: 1160430.004613 6032, 6034, and 6036, respectively; (iii-4) SEQ ID NOS: 6042, 6044, and 6046, respectively; (iii-5) SEQ ID NOS: 6052, 6054, and 6056, respectively; (iii-6) SEQ ID NOS: 6062, 6064, and 6066, respectively; (iii-7) SEQ ID NOS: 6072, 6074, and 6076, respectively; (iii-8) SEQ ID NOS: 6082, 6084, and 6086, respectively; (iii-9) SEQ ID NOS: 6092, 6094, and 6096, respectively; (iii-10) SEQ ID NOS: 6102, 6104, and 6106, respectively; (iii-11) SEQ ID NOS: 6112, 6114, and 6116, respectively; (iii-12) SEQ ID NOS: 6122, 6124, and 6126, respectively; (iii-13) SEQ ID NOS: 6132, 6134, and 6136, respectively; (iii-14) SEQ ID NOS: 6142, 6144, and 6146, respectively; (iii-15) SEQ ID NOS: 6152, 6154, and 6156, respectively; (iii-16) SEQ ID NOS: 6162, 6164, and 6166, respectively; (iii-17) SEQ ID NOS: 6172, 6174, and 6176, respectively; (iii-18) SEQ ID NOS: 6182, 6184, and 6186, respectively; (iii-19) SEQ ID NOS: 6192, 6194, and 6196, respectively; (iii-20) SEQ ID NOS: 6202, 6204, and 6206, respectively; (iii-21) SEQ ID NOS: 6212, 6214, and 6216, respectively; (iii-22) SEQ ID NOS: 6222, 6224, and 6226, respectively; (iii-23) SEQ ID NOS: 6232, 6234, and 6236, respectively; (iii-24) SEQ ID NOS: 6242, 6244, and 6246, respectively; (iii-25) SEQ ID NOS: 6252, 6254, and 6256, respectively; (iii-26) SEQ ID NOS: 6262, 6264, and 6266, respectively; (iii-27) SEQ ID NOS: 6272, 6274, and 6276, respectively; (iii-28) SEQ ID NOS: 6282, 6284, and 6286, respectively; (iii-29) SEQ ID NOS: 6292, 6294, and 6296, respectively; (iii-30) SEQ ID NOS: 6302, 6304, and 6306, respectively; (iii-31) SEQ ID NOS: 6312, 6314, and 6316, respectively; (iii-32) SEQ ID NOS: 6322, 6324, and 6326, respectively; (iii-33) SEQ ID NOS: 6332, 6334, and 6336, respectively; (iii-34) SEQ ID NOS: 6342, 6344, and 6346, respectively; (iii-35) SEQ ID NOS: 6352, 6354, and 6356, respectively; (iii-36) SEQ ID NOS: 6362, 6364, and 6366, respectively; (iii-37) SEQ ID NOS: 6372, 6374, and 6376, respectively; (iii-38) SEQ ID NOS: 6382, 6384, and 6386, respectively; (iii-39) SEQ ID NOS: 6392, 6394, and 6396, respectively; (iii-40) SEQ ID NOS: 6402, 6404, and 6406, respectively; (iii-41) SEQ ID NOS: 6412, 6414, and 6416, respectively; (iii-42) SEQ ID NOS: 6422, 6424, and 6426, respectively; (iii-43) SEQ ID NOS: 6432, 6434, and 6436, respectively; (iii-44) SEQ ID NOS: 6442, 6444, and 6446, respectively; (iii-45) SEQ ID NOS: 6452, 6454, and 6456, respectively; (iii-46) SEQ ID NOS: 6462, 6464, and 6466, respectively; (iii-47) SEQ ID NOS: 6472, 6474, and 6476, respectively; or (iii-48) SEQ ID NOS: 6482, 6484, and 6486, respectively.

[0033] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid 13 Attorney Docket No.: 1160430.004613 sequences of: SEQ ID NOS: 7012, 7014, and 7016, respectively, SEQ ID NOS: 7062, 7064, and 7066, respectively, SEQ ID NOS: 7132, 7134, and 7136, respectively, or SEQ ID NOS: 7162, 7164, and 7166, respectively, or any of (iv-1) SEQ ID NOS: 7012, 7014, and 7016, respectively; (iv-2) SEQ ID NOS: 7022, 7024, and 7026, respectively; (iv-3) SEQ ID NOS: 7032, 7034, and 7036, respectively; (iv-4) SEQ ID NOS: 7042, 7044, and 7046, respectively; (iv-5) SEQ ID NOS: 7052, 7054, and 7056, respectively; (iv-6) SEQ ID NOS: 7062, 7064, and 7066, respectively; (iv-7) SEQ ID NOS: 7072, 7074, and 7076, respectively; (iv-8) SEQ ID NOS: 7082, 7084, and 7086, respectively; (iv-9) SEQ ID NOS: 7092, 7094, and 7096, respectively; (iv-10) SEQ ID NOS: 7102, 7104, and 7106, respectively; (iv-11) SEQ ID NOS: 7112, 7114, and 7116, respectively; (iv-12) SEQ ID NOS: 7122, 7124, and 7126, respectively; (iv-13) SEQ ID NOS: 7132, 7134, and 7136, respectively; (iv-14) SEQ ID NOS: 7142, 7144, and 7146, respectively; (iv-15) SEQ ID NOS: 7152, 7154, and 7156, respectively; (iv-16) SEQ ID NOS: 7162, 7164, and 7166, respectively; (iv-17) SEQ ID NOS: 7172, 7174, and 7176, respectively; (iv-18) SEQ ID NOS: 7182, 7184, and 7186, respectively; (iv-19) SEQ ID NOS: 7192, 7194, and 7196, respectively; (iv-20) SEQ ID NOS: 7202, 7204, and 7206, respectively; (iv-21) SEQ ID NOS: 7212, 7214, and 7216, respectively; (iv-22) SEQ ID NOS: 7222, 7224, and 7226, respectively; (iv-23) SEQ ID NOS: 7232, 7234, and 7236, respectively; (iv-24) SEQ ID NOS: 7242, 7244, and 7246, respectively; (iv-25) SEQ ID NOS: 7252, 7254, and 7256, respectively; (iv-26) SEQ ID NOS: 7262, 7264, and 7266, respectively; (iv-27) SEQ ID NOS: 7272, 7274, and 7276, respectively; (iv-28) SEQ ID NOS: 7282, 7284, and 7286, respectively; or (iv-29) SEQ ID NOS: 7292, 7294, and 7296, respectively.

[0034] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences of: SEQ ID NOS: 8032, 8034, and 8036, respectively, or SEQ ID NOS: 8292, 8294, and 8296, respectively, or any of (v-1) SEQ ID NOS: 8012, 8014, and 8016, respectively; (v-2) SEQ ID NOS: 8022, 8024, and 8026, respectively; (v-3) SEQ ID NOS: 8032, 8034, and 8036, respectively; (v-4) SEQ ID NOS: 8042, 8044, and 8046, respectively; (v-5) SEQ ID NOS: 8052, 8054, and 8056, respectively; (v-6) SEQ ID NOS: 8062, 8064, and 8066, respectively; (v-7) SEQ ID NOS: 8072, 8074, and 8076, respectively; (v-8) SEQ ID NOS: 8082, 8084, and 8086, respectively; (v-9) SEQ ID NOS: 8092, 8094, and 8096, respectively; (v-10) SEQ ID NOS: 8102, 8104, and 8106, respectively; (v-11) SEQ ID NOS: 8112, 8114, and 8116, respectively; (v-12) SEQ ID NOS: 8122, 8124, and 8126, respectively; 14 Attorney Docket No.: 1160430.004613 (v-13) SEQ ID NOS: 8132, 8134, and 8136, respectively; (v-14) SEQ ID NOS: 8142, 8144, and 8146, respectively; (v-15) SEQ ID NOS: 8152, 8154, and 8156, respectively; (v-16) SEQ ID NOS: 8162, 8164, and 8166, respectively; (v-17) SEQ ID NOS: 8172, 8174, and 8176, respectively; (v-18) SEQ ID NOS: 8182, 8184, and 8186, respectively; (v-19) SEQ ID NOS: 8192, 8194, and 8196, respectively; (v-20) SEQ ID NOS: 8202, 8204, and 8206, respectively; (v-21) SEQ ID NOS: 8212, 8214, and 8216, respectively; (v-22) SEQ ID NOS: 8222, 8224, and 8226, respectively; (v-23) SEQ ID NOS: 8232, 8234, and 8236, respectively; (v-24) SEQ ID NOS: 8242, 8244, and 8246, respectively; (v-25) SEQ ID NOS: 8252, 8254, and 8256, respectively; (v-26) SEQ ID NOS: 8262, 8264, and 8266, respectively; (v-27) SEQ ID NOS: 8272, 8274, and 8276, respectively; (v-28) SEQ ID NOS: 8282, 8284, and 8286, respectively; (v-29) SEQ ID NOS: 8292, 8294, and 8296, respectively; (v-30) SEQ ID NOS: 8302, 8304, and 8306, respectively; (v-31) SEQ ID NOS: 8312, 8314, and 8316, respectively; or (v-32) SEQ ID NOS: 8322, 8324, and 8326, respectively.

[0035] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences of: SEQ ID NOS: 9032, 9034, and 9036, respectively, or SEQ ID NOS: 9122, 9124, and 9126, respectively, or any of (vi-1) SEQ ID NOS: 9012, 9014, and 9016, respectively; (vi-2) SEQ ID NOS: 9022, 9024, and 9026, respectively; (vi-3) SEQ ID NOS: 9032, 9034, and 9036, respectively; (vi-4) SEQ ID NOS: 9042, 9044, and 9046, respectively; (vi-5) SEQ ID NOS: 9052, 9054, and 9056, respectively; (vi-6) SEQ ID NOS: 9062, 9064, and 9066, respectively; (vi-7) SEQ ID NOS: 9072, 9074, and 9076, respectively; (vi-8) SEQ ID NOS: 9082, 9084, and 9086, respectively; (vi-9) SEQ ID NOS: 9092, 9094, and 9096, respectively; (vi-10) SEQ ID NOS: 9102, 9104, and 9106, respectively; (vi-11) SEQ ID NOS: 9112, 9114, and 9116, respectively; (vi-12) SEQ ID NOS: 9122, 9124, and 9126, respectively; (vi-13) SEQ ID NOS: 9132, 9134, and 9136, respectively; (vi-14) SEQ ID NOS: 9142, 9144, and 9146, respectively; (vi-15) SEQ ID NOS: 9152, 9154, and 9156, respectively; (vi-16) SEQ ID NOS: 9162, 9164, and 9166, respectively; (vi-17) SEQ ID NOS: 9172, 9174, and 9176, respectively; (vi-18) SEQ ID NOS: 9182, 9184, and 9186, respectively; (vi-19) SEQ ID NOS: 9192, 9194, and 9196, respectively; (vi-20) SEQ ID NOS: 9202, 9204, and 9206, respectively; (vi-21) SEQ ID NOS: 9212, 9214, and 9216, respectively; (vi-22) SEQ ID NOS: 9222, 9224, and 9226, respectively; (vi-23) SEQ ID NOS: 9232, 9234, and 9236, respectively; (vi-24) SEQ ID NOS: 9242, 9244, and 9246, respectively; (vi-25) SEQ ID NOS: 9252, 9254, and 9256, respectively; (vi-26) SEQ ID 15 Attorney Docket No.: 1160430.004613 NOS: 9262, 9264, and 9266, respectively; (vi-27) SEQ ID NOS: 9272, 9274, and 9276, respectively; or (vi-28) SEQ ID NOS: 9282, 9284, and 9286, respectively.

[0036] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences of: (i) SEQ ID NOS: 112, 114, and 116, respectively; (ii) SEQ ID NOS: 212, 214, and 216, respectively; (iii) SEQ ID NOS: 312, 314, and 316, respectively; (iv) SEQ ID NOS: 412, 414, and 416, respectively; (v) SEQ ID NOS: 512, 514, and 516, respectively; (vi) SEQ ID NOS: 612, 614, and 616, respectively; (vii) SEQ ID NOS: 712, 714, and 716, respectively; (viii) SEQ ID NOS: 812, 814, and 816, respectively; (ix) SEQ ID NOS: 912, 914, and 916, respectively; (x) SEQ ID NOS: 1012, 1014, and 1016, respectively; (xi) SEQ ID NOS: 1112, 1114, and 1116, respectively; (xii) SEQ ID NOS: 1212, 1214, and 1216, respectively; (xiii) SEQ ID NOS: 1312, 1314, and 1316, respectively; (xiv) SEQ ID NOS: 1412, 1414, and 1416, respectively; (xv) SEQ ID NOS: 1512, 1514, and 1516, respectively; (xvi) SEQ ID NOS: 1612, 1614, and 1616, respectively; (xvii) SEQ ID NOS: 1712, 1714, and 1716, respectively; (xviii) SEQ ID NOS: 1812, 1814, and 1816, respectively; (xix) SEQ ID NOS: 1912, 1914, and 1916, respectively; (xx) SEQ ID NOS: 2012, 2014, and 2016, respectively; (xxi) SEQ ID NOS: 2112, 2114, and 2116, respectively; (xxii) SEQ ID NOS: 2212, 2214, and 2216, respectively; (xxiii) SEQ ID NOS: 2312, 2314, and 2316, respectively; (xxiv) SEQ ID NOS: 2412, 2414, and 2416, respectively; (xxv) SEQ ID NOS: 2512, 2514, and 2516, respectively; (xxvi) SEQ ID NOS: 2612, 2614, and 2616, respectively; (xxvii) SEQ ID NOS: 2712, 2714, and 2716, respectively; (xxviii) SEQ ID NOS: 2812, 2814, and 2816, respectively; (xxix) SEQ ID NOS: 2912, 2914, and 2916, respectively; or (xxx) SEQ ID NOS: 3012, 3014, and 3016, respectively.

[0037] In some embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 may comprise or consist of: the CDR1, CDR2, and CDR3 amino acid sequences of: (xxxi) SEQ ID NOS: 10112, 10114, and 10116, respectively; (xxxii) SEQ ID NOS: 10212, 10214, and 10216, respectively; (xxxiii) SEQ ID NOS: 10312, 10314, and 10316, respectively; (xxxiv) SEQ ID NOS: 10412, 10414, and 10416, respectively; (xxxv) SEQ ID NOS: 10512, 10514, and 10516, respectively; (xxxvi) SEQ ID NOS: 10612, 10614, and 10616, respectively; (xxxvii) SEQ ID NOS: 10712, 10714, and 10716, respectively; (xxxviii) SEQ ID NOS: 10812, 10814, and 10816, respectively; (xxxix) SEQ ID NOS: 10912, 10914, and 10916, respectively; (xl) SEQ ID NOS: 11012, 11014, and 11016, respectively; (xli) SEQ ID NOS: 11112, 11114, and 11116, respectively; (xlii) SEQ ID NOS: 16 Attorney Docket No.: 1160430.004613 11212, 11214, and 11216, respectively; (xliii) SEQ ID NOS: 11312, 11314, and 11316, respectively; (xliv) SEQ ID NOS: 11412, 11414, and 11416, respectively; (xlv) SEQ ID NOS: 11512, 11514, and 11516, respectively; (xlvi) SEQ ID NOS: 11612, 11614, and 11616, respectively; (xlvii) SEQ ID NOS: 11712, 11714, and 11716, respectively; or (xlviii) SEQ ID NOS: 11812, 11814, and 11816, respectively.

[0038] In certain embodiments, the amino acid sequence of the VH-1 may comprise or consist of: (a) the VHH amino acid sequence of: SEQ ID NO: 4140 or any of (i-1) SEQ ID NO: 4010; (i-2) SEQ ID NO: 4020; (i-3) SEQ ID NO: 4030; (i-4) SEQ ID NO: 4040; (i-5) SEQ ID NO: 4050; (i-6) SEQ ID NO: 4060; (i-7) SEQ ID NO: 4070; (i-8) SEQ ID NO: 4080; (i-9) SEQ ID NO: 4090; (i-10) SEQ ID NO: 4100; (i-11) SEQ ID NO: 4110; (i-12) SEQ ID NO: 4120; (i-13) SEQ ID NO: 4130; (i-14) SEQ ID NO: 4140; (i-15) SEQ ID NO: 4150; (i- 16) SEQ ID NO: 4160; (i-17) SEQ ID NO: 4170; (i-18) SEQ ID NO: 4180; (i-19) SEQ ID NO: 4190; (i-20) SEQ ID NO: 4200; (i-21) SEQ ID NO: 4210; (i-22) SEQ ID NO: 4220; (i- 23) SEQ ID NO: 4230; (i-24) SEQ ID NO: 4240; (i-25) SEQ ID NO: 4250; (i-26) SEQ ID NO: 4260; (i-27) SEQ ID NO: 4270; (i-28) SEQ ID NO: 4280; (i-29) SEQ ID NO: 4290; (i- 30) SEQ ID NO: 4300; (i-31) SEQ ID NO: 4310; (i-32) SEQ ID NO: 4320; (i-33) SEQ ID NO: 4330; (i-34) SEQ ID NO: 4340; (i-35) SEQ ID NO: 4350; (i-36) SEQ ID NO: 4360; (i- 37) SEQ ID NO: 4370; (i-38) SEQ ID NO: 4380; (i-39) SEQ ID NO: 4390; (i-40) SEQ ID NO: 4400; (i-41) SEQ ID NO: 4410; (i-42) SEQ ID NO: 4420; (i-43) SEQ ID NO: 4430; or (i-44) SEQ ID NO: 4440; or (b) a variant thereof having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to said VHH amino acid sequence.

[0039] In certain embodiments, the amino acid sequence of the VH-1 may comprise or consist of: (a) the VHH amino acid sequence of: SEQ ID NO: 5010, 5100, or 5190, or any of (ii-1) SEQ ID NO: 5010; (ii-2) SEQ ID NO: 5020; (ii-3) SEQ ID NO: 5030; (ii-4) SEQ ID NO: 5040; (ii-5) SEQ ID NO: 5050; (ii-6) SEQ ID NO: 5060; (ii-7) SEQ ID NO: 5070; (ii-8) SEQ ID NO: 5080; (ii-9) SEQ ID NO: 5090; (ii-10) SEQ ID NO: 5100; (ii-11) SEQ ID NO: 5110; (ii-12) SEQ ID NO: 5120; (ii-13) SEQ ID NO: 5130; (ii-14) SEQ ID NO: 5140; (ii-15) SEQ ID NO: 5150; (ii-16) SEQ ID NO: 5160; (ii-17) SEQ ID NO: 5170; (ii-18) SEQ ID NO: 5180; (ii-19) SEQ ID NO: 5190; (ii-20) SEQ ID NO: 5200; (ii-21) SEQ ID NO: 5210; (ii-22) SEQ ID NO: 5220; (ii-23) SEQ ID NO: 5230; (ii-24) SEQ ID NO: 5240; (ii-25) SEQ ID NO: 5250; (ii-26) SEQ ID NO: 5260; (ii-27) SEQ ID NO: 5270; (ii-28) SEQ ID NO: 5280; (ii-29) SEQ ID NO: 5290; (ii-30) SEQ ID NO: 5300; (ii-31) SEQ ID NO: 5310; (ii-32) SEQ ID NO: 17 Attorney Docket No.: 1160430.004613 5320; (ii-33) SEQ ID NO: 5330; or (ii-34) SEQ ID NO: 5340; or (b) a variant thereof having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to said VHH amino acid sequence.

[0040] In certain embodiments, the amino acid sequence of the VH-1 may comprise or consist of: (a) the VHH amino acid sequence of: SEQ ID NO: 6040, 6010, 6190, or 6270, or any of (iii-1) SEQ ID NO: 6010; (iii-2) SEQ ID NO: 6020; (iii-3) SEQ ID NO: 6030; (iii-4) SEQ ID NO: 6040; (iii-5) SEQ ID NO: 6050; (iii-6) SEQ ID NO: 6060; (iii-7) SEQ ID NO: 6070; (iii-8) SEQ ID NO: 6080; (iii-9) SEQ ID NO: 6090; (iii-10) SEQ ID NO: 6100; (iii-11) SEQ ID NO: 6110; (iii-12) SEQ ID NO: 6120; (iii-13) SEQ ID NO: 6130; (iii-14) SEQ ID NO: 6140; (iii-15) SEQ ID NO: 6150; (iii-16) SEQ ID NO: 6160; (iii-17) SEQ ID NO: 6170; (iii-18) SEQ ID NO: 6180; (iii-19) SEQ ID NO: 6190; (iii-20) SEQ ID NO: 6200; (iii-21) SEQ ID NO: 6210; (iii-22) SEQ ID NO: 6220; (iii-23) SEQ ID NO: 6230; (iii-24) SEQ ID NO: 6240; (iii-25) SEQ ID NO: 6250; (iii-26) SEQ ID NO: 6260; (iii-27) SEQ ID NO: 6270; (iii-28) SEQ ID NO: 6280; (iii-29) SEQ ID NO: 6290; (iii-30) SEQ ID NO: 6300; (iii-31) SEQ ID NO: 6310; (iii-32) SEQ ID NO: 6320; (iii-33) SEQ ID NO: 6330; (iii-34) SEQ ID NO: 6340; (iii-35) SEQ ID NO: 6350; (iii-36) SEQ ID NO: 6360; (iii-37) SEQ ID NO: 6370; (iii-38) SEQ ID NO: 6380; (iii-39) SEQ ID NO: 6390; (iii-40) SEQ ID NO: 6400; (iii-41) SEQ ID NO: 6410; (iii-42) SEQ ID NO: 6420; (iii-43) SEQ ID NO: 6430; (iii-44) SEQ ID NO: 6440; (iii-45) SEQ ID NO: 6450; (iii-46) SEQ ID NO: 6460; (iii-47) SEQ ID NO: 6470; or (iii-48) SEQ ID NO: 6480; or (b) a variant thereof having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to said VHH amino acid sequence.

[0041] In certain embodiments, the amino acid sequence of the VH-1 may comprise or consist of: (a) the VHH amino acid sequence of: SEQ ID NO: 7010, 7060, 7130, or 7160, or any of (iv-1) SEQ ID NO: 7010; (iv-2) SEQ ID NO: 7020; (iv-3) SEQ ID NO: 7030; (iv-4) SEQ ID NO: 7040; (iv-5) SEQ ID NO: 7050; (iv-6) SEQ ID NO: 7060; (iv-7) SEQ ID NO: 7070; (iv-8) SEQ ID NO: 7080; (iv-9) SEQ ID NO: 7090; (iv-10) SEQ ID NO: 7100; (iv-11) SEQ ID NO: 7110; (iv-12) SEQ ID NO: 7120; (iv-13) SEQ ID NO: 7130; (iv-14) SEQ ID NO: 7140; (iv-15) SEQ ID NO: 7150; (iv-16) SEQ ID NO: 7160; (iv-17) SEQ ID NO: 7170; (iv-18) SEQ ID NO: 7180; (iv-19) SEQ ID NO: 7190; (iv-20) SEQ ID NO: 7200; (iv-21) SEQ ID NO: 7210; (iv-22) SEQ ID NO: 7220; (iv-23) SEQ ID NO: 7230; (iv-24) SEQ ID NO: 7240; (iv-25) SEQ ID NO: 7250; (iv-26) SEQ ID NO: 7260; (iv-27) SEQ ID NO: 7270; (iv-28) SEQ ID NO: 7280; or (iv-29) SEQ ID NO: 7290; or (b) a variant thereof having at 18 Attorney Docket No.: 1160430.004613 least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to said VHH amino acid sequence.

[0042] In certain embodiments, the amino acid sequence of the VH-1 may comprise or consist of: (a) the VHH amino acid sequence of: SEQ ID NO: 8030 or 8290, or any of (v-1) SEQ ID NO: 8010; (v-2) SEQ ID NO: 8020; (v-3) SEQ ID NO: 8030; (v-4) SEQ ID NO: 8040; (v-5) SEQ ID NO: 8050; (v-6) SEQ ID NO: 8060; (v-7) SEQ ID NO: 8070; (v-8) SEQ ID NO: 8080; (v-9) SEQ ID NO: 8090; (v-10) SEQ ID NO: 8100; (v-11) SEQ ID NO: 8110; (v-12) SEQ ID NO: 8120; (v-13) SEQ ID NO: 8130; (v-14) SEQ ID NO: 8140; (v-15) SEQ ID NO: 8150; (v-16) SEQ ID NO: 8160; (v-17) SEQ ID NO: 8170; (v-18) SEQ ID NO: 8180; (v-19) SEQ ID NO: 8190; (v-20) SEQ ID NO: 8200; (v-21) SEQ ID NO: 8210; (v-22) SEQ ID NO: 8220; (v-23) SEQ ID NO: 8230; (v-24) SEQ ID NO: 8240; (v-25) SEQ ID NO: 8250; (v-26) SEQ ID NO: 8260; (v-27) SEQ ID NO: 8270; (v-28) SEQ ID NO: 8280; (v-29) SEQ ID NO: 8290; (v-30) SEQ ID NO: 8300; (v-31) SEQ ID NO: 8310; or (v-32) SEQ ID NO: 8320; or (b) a variant thereof having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to said VHH amino acid sequence.

[0043] In certain embodiments, the amino acid sequence of the VH-1 may comprise or consist of: (a) the VHH amino acid sequence of: SEQ ID NO: 9030 or 9120, or any of (vi-1) SEQ ID NO: 9010; (vi-2) SEQ ID NO: 9020; (vi-3) SEQ ID NO: 9030; (vi-4) SEQ ID NO: 9040; (vi-5) SEQ ID NO: 9050; (vi-6) SEQ ID NO: 9060; (vi-7) SEQ ID NO: 9070; (vi-8) SEQ ID NO: 9080; (vi-9) SEQ ID NO: 9090; (vi-10) SEQ ID NO: 9100; (vi-11) SEQ ID NO: 9110; (vi-12) SEQ ID NO: 9120; (vi-13) SEQ ID NO: 9130; (vi-14) SEQ ID NO: 9140; (vi- 15) SEQ ID NO: 9150; (vi-16) SEQ ID NO: 9160; (vi-17) SEQ ID NO: 9170; (vi-18) SEQ ID NO: 9180; (vi-19) SEQ ID NO: 9190; (vi-20) SEQ ID NO: 9200; (vi-21) SEQ ID NO: 9210; (vi-22) SEQ ID NO: 9220; (vi-23) SEQ ID NO: 9230; (vi-24) SEQ ID NO: 9240; (vi- 25) SEQ ID NO: 9250; (vi-26) SEQ ID NO: 9260; (vi-27) SEQ ID NO: 9270; or (vi-28) SEQ ID NO: 9280; or (b) a variant thereof having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to said VHH amino acid sequence.

[0044] In certain embodiments, the amino acid sequence of the VH-1 may comprise or consist of: (a) the VHH amino acid sequence of: SEQ ID NO: 2110, 410, 1410, 1510, 1910, 2210, 2510, or 2710, or any of (i) SEQ ID NOS: 110; (ii) SEQ ID NO: 210; (iii) SEQ ID NO: 310; (iv) SEQ ID NO: 410; (v) SEQ ID NO: 510; (vi) SEQ ID NO: 610; (vii) SEQ ID NO: 710; (viii) SEQ ID NO: 810; (ix) SEQ ID NO: 910; (x) SEQ ID NO: 1010; (xi) SEQ ID NO: 1110; (xii) SEQ ID NO: 1210; (xiii) SEQ ID NO: 1310; (xiv) SEQ ID NO: 1410; (xv) SEQ 19 Attorney Docket No.: 1160430.004613 ID NO: 1510; (xvi) SEQ ID NO: 1610; (xvii) SEQ ID NO: 1710; (xviii) SEQ ID NO: 1810; (xix) SEQ ID NO: 1910; (xx) SEQ ID NO: 2010; (xxi) SEQ ID NO: 2110; (xxii) SEQ ID NO: 2210; (xxiii) SEQ ID NO: 2310; (xxiv) SEQ ID NO: 2410; (xxv) SEQ ID NO: 2510; (xxvi) SEQ ID NO: 2610; (xxvii) SEQ ID NO: 2710; (xxviii) SEQ ID NO: 2810; (xxix) SEQ ID NO: 2910; or (xxx) SEQ ID NO: 3010; or (b) a variant thereof having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to said VHH amino acid sequence.

[0045] In certain embodiments, the amino acid sequence of the VH-1 may comprise or consist of: (a) the VHH amino acid sequence of: (xxxi) SEQ ID NOS: 10110; (xxxii) SEQ ID NO: 10210; (xxxiii) SEQ ID NO: 10310; (xxxiv) SEQ ID NO: 10410; (xxxv) SEQ ID NO: 10510; (xxxvi) SEQ ID NO: 10610; (xxxvii) SEQ ID NO: 10710; (xxxviii) SEQ ID NO: 10810; (xxxix) SEQ ID NO: 10910; (xl) SEQ ID NO: 11010; (xli) SEQ ID NO: 11110; (xlii) SEQ ID NO: 11210; (xliii) SEQ ID NO: 11310; (xliv) SEQ ID NO: 11410; (xlv) SEQ ID NO: 11510; (xlvi) SEQ ID NO: 11610; (xlvii) SEQ ID NO: 11710; or (xlviii) SEQ ID NO: 11810; or (b) a variant thereof having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to said VHH amino acid sequence.

[0046] The VH-1 may comprise: (a) a first heavy chain framework region (FR) 1 (FRH1-1); (b) a first heavy chain FR2 (FRH2-1); (c) a first heavy chain FR3 (FRH3-1); (d) a first heavy chain FR4 (FRH4-1).

[0047] In some embodiments, the VH-1 may be partially or fully humanized.

[0048] In some embodiments, the VH-1 may be humanized except for the FRH2-1.

[0049] In some embodiments, the VH-1 may be humanized but the sequence may not be altered at certain amino acid positions, i.e., maintaining amino acids found in llama VHH sequences. In certain embodiments, maintaining llama VHH sequences at certain amino acid positions may help maintain CDR conformations.

[0050] In some embodiments, the VH-1 may be humanized but comprises one or more of F or Y at position 37, E or Q at position 44, and / or R at position 45, wherein the position is according to Kabat or Martin numbering.

[0051] In some embodiments, the VH-1 may be humanized but comprises one or more of F or Y at position 42, E or Q at position 49, and / or R at position 50, wherein the position is according to IMGT numbering. 20 Attorney Docket No.: 1160430.004613

[0052] In certain embodiments, the VH-1 may comprise one or more amino acids or one or more amino acid modifications (assuming the parent antibody has a different amino acid at the recited position or positions) wherein said modifications are at one or more positions selected from the following: E or Q at position 1; V or L at position 5; L or V at position 11; Q or K at position 13; P at position 14; G or R at position 16; R at position 19; A at position 23; A at position 24; F at position 27; V at position 37; G at position 44; L at position 45; E or V at position 46; W at position 47; S or A at position 49; A or V at position 60; T at position 68; I or V at position 69; N or D at position 73; S or A at position 74; T or S at position 77; L or V at position 78; S at position 82b; R at position 83; A, V, or P at position 84; E or D at position 85; V or L at position 89; A or V at position 93; R, K, or T at position 94; and / or L, T, or M at position 108, wherein the position is according to Kabat numbering.

[0053] In certain embodiments, the VH-1 may comprise one or more amino acids or one or more amino acid modifications (assuming the parent antibody has a different amino acid at the recited position or positions) wherein said modifications are at one or more positions selected from the following: (P at position 14; F at position 27; V at position 37; G at position 44; L at position 45; W at position 47; L at position 78; R at position 83; A at position 84; R or K at position 94; and / or L at position 108, wherein the position is according to Kabat numbering.

[0054] In certain embodiments, the VH-1 may comprise at least one of: V at position 37; G at position 44; L at position 45; and / or W at position 47, wherein the position is according to Kabat numbering.

[0055] In particular embodiments, the VH-1 may comprise one or more amino acids or one or more amino acid modifications (assuming the parent antibody has a different amino acid at the recited position or positions) according to Kabat numbering described above, while comprising one or more of F or Y at position 37, E or Q at position 44, and / or R at position 45, wherein the position is according to Kabat numbering.

[0056] In certain embodiments, the VH-1 may comprise one or more amino acids or one or more amino acid modifications (assuming the parent antibody has a different amino acid at the recited position or positions) wherein said modifications are at one or more positions selected from the following: E or Q at position 1; V or L at position 5; L or V at position 11; Q or K at position 13; P at position 14; G or R at position 16; R at position 19; A at position 23; A at position 24; F at position 27; V at position 37; G at position 44; L at position 45; E 21 Attorney Docket No.: 1160430.004613 or V at position 46; W at position 47; S or A at position 49; A or V at position 60; T at position 68; I or V at position 69; N or D at position 72a; S or A at position 72b; T or S at position 74; L or V at position 75; S at position 81; R at position 83; A, V, or P at position 84; E or D at position 85; V or L at position 89; A or V at position 93; R, K, or T at position 94; and / or L, T, or M at position 108, wherein the position is according to Martin numbering.

[0057] In certain embodiments, the VH-1 comprises one or more amino acids or one or more amino acid modifications (assuming the parent antibody has a different amino acid at the recited position or positions) wherein said modifications are at one or more positions selected from the following: P at position 14; F at position 27; V at position 37; G at position 44; L at position 45; W at position 47; L at position 75; R at position 83; A at position 84; R or K at position 94; and / or L at position 108, wherein the position is according to Martin numbering.

[0058] In certain embodiments, the VH-1 may comprise at least one of: V at position 37; G at position 44; L at position 45; and / or W at position 47, wherein the position is according to Martin numbering.

[0059] In particular embodiments, the VH-1 may comprise one or more amino acids or one or more amino acid modifications (assuming the parent antibody has a different amino acid at the recited position or positions) according to Martin numbering described above, while comprising one or more of F or Y at position 37, E or Q at position 44, and / or R at position 45, wherein the position is according to Martin numbering.

[0060] In certain embodiments, the VH-1 may comprise one or more amino acids or one or more amino acid modifications (assuming the parent antibody has a different amino acid at the recited position or positions) wherein said modifications are at one or more positions selected from the following: E or Q at position 1; V or L at position 5; L or V at position 12; Q or K at position 14; P at position 15; G or R at position 17; R at position 20; A at position 24; A at position 25; F at position 28; V at position 42; G at position 49; L at position 50; E or V at position 51; W at position 52; S or A at position 54; A or V at position 68; T at position 77; I or V at position 78; N or D at position 82; S or A at position 83; T or S at position 86; L or V at position 87; S at position 93; R at position 95; A, V, or P at position 96; E or D at position 97; V or L at position 101; A or V at position 105; R, K, or T at position 106; and / or L, T, or M at position 123, wherein the position is according to IMGT numbering. 22 Attorney Docket No.: 1160430.004613

[0061] In certain embodiments, the VH-1 comprises one or more amino acids or one or more amino acid modifications (assuming the parent antibody has a different amino acid at the recited position or positions) wherein said modifications are at one or more positions selected from the following: P at position 15; F at position 28; V at position 42; G at position 49; L at position 50; W at position 52; L at position 87; R at position 95; A at position 96; R or K at position 106; and / or L at position 123, wherein the position is according to IMGT numbering.

[0062] In certain embodiments, the VH-1 may comprise at least one of: V at position 42; G at position 49; L at position 50; and / or W at position 52, wherein the position is according to IMGT numbering.

[0063] In particular embodiments, the VH-1 may comprise one or more amino acids or one or more amino acid modifications (assuming the parent antibody has a different amino acid at the recited position or positions) according to IMGT numbering described above while comprising one or more of F or Y at position 42, E or Q at position 49, and / or R at position 50, wherein the position is according to IMGT numbering.

[0064] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.21, and or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.21 in Table 13C.

[0065] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9412, 9414, and 9416, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2X3SGX4X5X6X7X8X9GX10SX11X12X13SCX14ASG (SEQ ID NO: 9411), wherein X1 is Q or E; X2 is V or L; X3 is E or Q; X4 is G or A; X5 is G or E; X6 is L or V; X7 is V or K; X8 is Q or K; X9 is A or P; X10 is G, R, or S; X11 is L or V; X12 is R or K; X13 is L or V; and X14 is A or K; the amino acid sequence of the FRH2-1 comprises or consists of WX1RX2X3PGX4QREX5X6X7(SEQ ID NO: 9413), wherein X1 is Y or V; X2 is R or Q; X3 is V or A; X4 is K or Q; X5 is L or W; X6 is V or M; and X7 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1X2IX3X4DX5X6X7X8X9X10YX11X12X13X14SLX15X16EDTAVYX17C (SEQ ID NO: 9415), wherein X1 is F or V; X2 is A or T ; X3 is S or T; X4 is R or A; X5 is N or E; X6 is V, A, or S; X7 is Q, K, or T; X8 is N or S; X9 is Q, S, or T; X10 is V, L, or A; X11 is L or M; X12 is Q or E; X13 is M or L; X14 is N or S; X15 is K or R; X16 is P, A, or S; and X17 is F or Y; 23 Attorney Docket No.: 1160430.004613 and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9417), wherein X1 is Q or L.

[0066] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.21, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.21 based on IGHV3 as provided in Table 13C.

[0067] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9422, 9424, and 9426, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of EVQLX1ESGGGLVQPGX2SLRLSCAASG (SEQ ID NO: 9421), wherein X1 is V or L; and X2 is G or R; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKQREX2VX3(SEQ ID NO: 9423), wherein X1 is Y or V; X2 is L or W; and X3 is A or S; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1X2NX3X4YLQMNSLRAEDTAVYX5C (SEQ ID NO: 9425), wherein X1 is S, V, or A; X2 is Q or K; X3 is T or S; X4 is V or L; and X5 is F or Y; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9427).

[0068] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.21, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.21 based on IGHV1 as provided in Table 13C.

[0069] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9432, 9434, and 9436, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9431); the amino acid sequence of the FRH2-1 comprises or consists of WYRQAPGQQRELMX1(SEQ ID NO: 9433), wherein X1 is A or G; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9435), wherein X1 is A or R; X2 is E or N; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9437).

[0070] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.4, and or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.4 in Table 13C.

[0071] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9512, 9514, and 9516, respectively, 24 Attorney Docket No.: 1160430.004613 and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2X3SX4X5X6X7X8X9PGX10SX11X12X13SCX14ASX15(SEQ ID NO: 9511), wherein X1 is E or Q; X2 is V or L; X3 is D, E, or Q; X4 is E or G; X5 is G or A; X6 is G or E; X7 is L or V; X8 is V or K; X9 is Q or K; X10 is G or S; X11 is L or V; X12 is R or K; X13 is L or V; X14 is V, A, or K; and X15 is A or G; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGX2EREX3X4X5(SEQ ID NO: 9513), wherein X1 is F or V; X2 is K or Q; X3 is F or W; X4 is V or M; and X5 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1TIX2X3DX4X5X6X7X8X9YX10X11X12X13X14LX15X16EDTAVYYC (SEQ ID NO: 9515), wherein X1 is F or V; X2 is A, S, or T; X3 is R or A; X4 is N or E; X5 is A or S; X6 is R, K, or T; X7 is S or N; X8 is T or S; X9 is V, L, or A; X10 is L or M; X11 is Q or E; X12 is M or L; X13 is D, N, or S; X14 is N or S; X15 is K or R; and X16 is P, A, or S; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGRGTX1VTVSX2(SEQ ID NO: 9517), wherein X1 is Q or L; and X2 is F or S.

[0072] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.4, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.4 based on IGHV3 as provided in Table 13C.

[0073] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9522, 9524, and 9526, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2ESGGGLVX3PGGSLRLSCAASX4(SEQ ID NO: 9521), wherein X1 is Q or E; X2 is V or L; X3 is K or Q; and X4 is G or A; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKEREX2VX3(SEQ ID NO: 9523), wherein X1 is F or V; X2 is F or W; and X3 is S or A; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1KX2X3X4YLQMNSLRAEDTAVYYC (SEQ ID NO: 9525), wherein X1 is A or S; X2 is N or S; X3 is S or T; and X4 is L or V; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGRGTLVTVSS (SEQ ID NO: 9527).

[0074] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.4, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.4 based on IGHV1 as provided in Table 13C.

[0075] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9532, 9534, and 9536, respectively, 25 Attorney Docket No.: 1160430.004613 and: the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9531); the amino acid sequence of the FRH2-1 comprises or consists of WFRQAPGQEREFMX1(SEQ ID NO: 9533), wherein X1 is A or G; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9535), wherein X1 is A or R; X2 is E or N; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGRGTLVTVSS (SEQ ID NO: 9537).

[0076] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.14, and or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.14 in Table 13C.

[0077] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9612, 9614, and 9616, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VX2LX3X4SGX5X6X7X8X9X10GX11SX12X13X14SCX15ASG (SEQ ID NO: 9611), wherein X1 is Q or E; X2 is H or Q; X3 is V or L; X4 is E or Q; X5 is G or A; X6 is G or E; X7 is L or V; X8 is V or K; X9 is Q or K; X10 is A or P; X11 is G, R or S; X12 is L or V;X13 is R or K; X14 is L or V; and X15 is A or K; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGX2QRX3X4X5X6(SEQ ID NO: 9613), wherein X1 is Y or V; X2 is K or Q; X3 is D or E; X4 is F or W; X5 is V or M; and X6 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1TIX2X3DX4X5X6X7X8X9YX10X11X12X13SLX14X15EDTAVYYC (SEQ ID NO: 9615), wherein X1 is F or V; X2 is S or T; X3 is R or A; X4 is N or E; X5 is A or S; X6 is K or T; X7 is N or S; X8 is T or S; X9 is V, L, or A; X10 is L or M; X11 is Q or E; X12 is M or L; X13 is N or S; X14 is K or R; and X15 is P, A, or S; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9617), wherein X1 is Q or L.

[0078] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.14, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.14 based on IGHV3 as provided in Table 13C.

[0079] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9622, 9624, and 9626, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of 26 Attorney Docket No.: 1160430.004613 X1VQLX2ESGGGLVX3PGX4SLRLSCAASG (SEQ ID NO: 9621), wherein X1 is Q or E; X2 is V or L; X3 is K or Q; and X4 is G or R; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKQRX2X3VX4(SEQ ID NO: 9623), wherein X1 is Y or V; X2 is D or E; X3 is F or W; and X4 is A or S; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1KNX2X3YLQMNSLX4X5EDTAVYYC (SEQ ID NO: 9625), wherein X1 is A or S; X2 is S or T; X3 is V or L; X4 is R or K; and X5 is P or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9627).

[0080] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.14, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.14 based on IGHV1 as provided in Table 13C.

[0081] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9632, 9634, and 9636, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9631); the amino acid sequence of the FRH2-1 comprises or consists of WYRQAPGQQREFMX1(SEQ ID NO: 9633), wherein X1 is G or A; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9635), wherein X1 is A or R; X2 is E or N; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9637).

[0082] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.15, and or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.15 in Table 13C.

[0083] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9712, 9714, and 9716, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2X3SGX4X5X6X7X8PGX9SX10X11X12SCX13ASG (SEQ ID NO: 9711), wherein X1 is E or Q; X2 is V or L; X3 is E or Q; X4 is G or A; X5 is G or E; X6 is S, L, or V; X7 is V or K; X8 is Q or K; X9 is G, R, or S; X10 is L or V; X11 is R or K; X12 is L or V; and X13 is L, A, or K; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGX2EREFX3X4(SEQ ID NO: 9713), wherein X1 is F or V; X2 is K or Q; X3 is V or M; and X4 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists 27 Attorney Docket No.: 1160430.004613 of RX1TIX2X3DX4X5X6X7X8X9YX10X11X12X13SLX14X15EDTAX16YYC (SEQ ID NO: 9715), wherein X1 is F or V; X2 is S or T; X3 is R or A; X4 is N or E; X5 is A or S; X6 is R, K, or T; X7 is T, N, or S; X8 is T or S; X9 is V, L, or A; X10 is L or M; X11 is R, Q, or E; X12 is M or L; X13 is D, N, or S; X14 is K or R; X15 is P, A, or S; and X16 is I or V; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9717), wherein X1 is Q or L.

[0084] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.15, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.15 based on IGHV3 as provided in Table 13C.

[0085] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9722, 9724, and 9726, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of EVQLX1ESGGGLVQPGX2SLRLSCAASG (SEQ ID NO: 9721), wherein X1 is L or V; and X2 is G or R; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKEREFVX2 (SEQ ID NO: 9723), wherein X1 is F or V; and X2 is S or A; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1X2X3X4X5YLQMNSLRX6EDTAVYYC (SEQ ID NO: 9725), wherein X1 is S or A; X2 is K or R; X3 is N or T; X4 is T or S; X5 is V or L; and X6 is A or P; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9727).

[0086] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.15, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.15 based on IGHV1 as provided in Table 13C.

[0087] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9732, 9734, and 9736, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9731); the amino acid sequence of the FRH2-1 comprises or consists of WFRQAPGQEREFMX1(SEQ ID NO: 9733), wherein X1 is A or G; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9735), wherein X1 is A or R; X2 is E or N; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9737). 28 Attorney Docket No.: 1160430.004613

[0088] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.19, and or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.19 in Table 13C.

[0089] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9812, 9814, and 9816, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2X3SGX4X5X6X7X8X9GX10SX11X12X13SCX14ASG (SEQ ID NO: 9811), wherein X1 is E or Q; X2 is V or L; X3 is E or Q; X4 is G or A; X5 is G or E; X6 is L or V; X7 is V or K; X8 is Q or K; X9 is A or P; X10 is G, R, or S; X11 is L or V; X12 is R or K; X13 is L or V; and X14 is E, A, or K; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGX2EREFX3X4(SEQ ID NO: 9813), wherein X1 is F or V; X2 is K or Q; X3 is V or M; and X4 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1TIX2X3DX4X5X6X7X8X9YX10X11X12X13SLX14X15EDTAX16YYC (SEQ ID NO: 9815), wherein X1 is F or V; X2 is T or S; X3 is R or A; X4 is N or E; X5 is A or S; X6 is K or T; X7 is K, N, or S; X8 is V, S, or T; X9 is V, L, or A; X10 is L or M; X11 is Q or E; X12 is M or L; X13 is S or N;X14 is K or R; X15 is P, A, or S; and X16 is A, V, or L; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9817), wherein X1 is Q, L, or T.

[0090] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.19, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.19 based on IGHV3 as provided in Table 13C.

[0091] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9822, 9824, and 9826, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of EVQLX1ESGGGLVQPGX2SLRLSCAASG (SEQ ID NO: 9821), wherein X1 is V or L; and X2 is R or G; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKEREFVX2(SEQ ID NO: 9823), wherein X1 is V or F; and X2 is S or A; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1KX2X3X4YLQMNSLX5X6EDTAX7YYC (SEQ ID NO: 9825), wherein X1 is A or S; X2 is N or K; X3 is S or T; X4 is V or L; X5 is R or K; X6 is A or P; and X7 is V or L; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9827), wherein X1 is L or T. 29 Attorney Docket No.: 1160430.004613

[0092] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.19, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.19 based on IGHV1 as provided in Table 13C.

[0093] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9832, 9834, and 9836, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9831); the amino acid sequence of the FRH2-1 comprises or consists of WFRQAPGQEREFMX1(SEQ ID NO: 9833), wherein X1 is G or A; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9835), wherein X1 is A or R; X2 is E or N; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9837).

[0094] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.25, and or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.25 in Table 13C.

[0095] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9912, 9914, and 9916, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2X3SX4X5X6X7X8X9X10GX11SX12X13X14SCX15ASG (SEQ ID NO: 9911), wherein X1 is E or Q; X2 is V or L; X3 is E or Q; X4 is K or G; X5 is G or A; X6 is G or E; X7 is L or V; X8 is V or K; X9 is Q or K; X10 is F or P; X11 is G or S; X12 is L or V; X13 is N, R, or K;X14 is L or V; and X15 is A, S, or K; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGX2EREFX3X4(SEQ ID NO: 9913), wherein X1 is F or V; X2 is K or Q; X3 is V or M; and X4 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1X2IX3X4DX5X6X7X8X9X10YX11X12X13X14SLX15X16EDTAVYYC (SEQ ID NO: 9915), wherein X1 is F or V; X2 is I or T; X3 is S or T; X4 is R or A; X5 is N or E; X6 is A or S; X7 is K or T; X8 is N or S; X9 is T or S; X10 is V, L, or A; X11 is L or M; X12 is Q or E; X13 is M or L;X14 is S or N; X15 is K or R; and X16 is P, A, or S; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9917), wherein X1 is Q or L. 30 Attorney Docket No.: 1160430.004613

[0096] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.25, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.25 based on IGHV3-23 as provided in Table 13C.

[0097] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9922, 9924, and 9926, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of EVQLLESGGGLVQPGGSLRLSCAASG (SEQ ID NO: 9921); the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKEREFVX2(SEQ ID NO: 9923), wherein X1 is F or V; and X2 is A or S; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1KNTX2YLQMNSLX3X4EDTAVYYC (SEQ ID NO: 9925), wherein X1 is A or S; X2 is V or L; X3 is R or K; and X4 is A or P; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9927).

[0098] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.25, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.25 based on IGHV3 as provided in Table 13C.

[0099] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9932, 9934, and 9936, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of EVQLX1ESGGGLVQPGGSLRLSCX2ASG (SEQ ID NO: 9931), wherein X1 is L or V; and X2 is A or S; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKEREFVX2(SEQ ID NO: 9933), wherein X1 is F or V; and X2 is A or S; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1KNX2X3YLQMX4SLX5X6EDTAVYYC (SEQ ID NO: 9935), wherein X1 is A or S; X2 is T or S; X3 is V or L; X4 is N or S; X5 is R or K; and X6 is A or P; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9937).

[0100] In some embodiments, the VH-1 may comprise the CDRs of Antibody No.25, and one or more of the FRs may comprise the corresponding consensus FR sequence(s) shared among humanized Antibody No.25 based on IGHV1 as provided in Table 13C.

[0101] In certain embodiments, the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9942, 9944, and 9946, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of 31 Attorney Docket No.: 1160430.004613 QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9941); the amino acid sequence of the FRH2-1 comprises or consists of WFRQAPGQEREFMX1(SEQ ID NO: 9943), wherein X1 is A or G; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9945), wherein X1 is R or A; X2 is N or E; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9947).

[0102] In particular embodiments, the amino acid sequence of the VH-1 may be the same as the VHH amino acid sequence of said first anti-CD3 antibody as listed in Table 13A, or as listed in Table 1A or 24A except that the VH-1 comprises one or more amino acids or one or more amino acid modifications, e.g., one or more listed above (assuming the parent antibody has a different amino acid at the recited position or positions).

[0103] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (i-1) SEQ ID NO: 4010; (i-2) SEQ ID NO: 4020; (i-3) SEQ ID NO: 4030; (i-4) SEQ ID NO: 4040; (i-5) SEQ ID NO: 4050; (i-6) SEQ ID NO: 4060; (i-7) SEQ ID NO: 4070; (i-8) SEQ ID NO: 4080; (i-9) SEQ ID NO: 4090; (i-10) SEQ ID NO: 4100; (i-11) SEQ ID NO: 4110; (i-12) SEQ ID NO: 4120; (i-13) SEQ ID NO: 4130; (i-14) SEQ ID NO: 4140; (i-15) SEQ ID NO: 4150; (i- 16) SEQ ID NO: 4160; (i-17) SEQ ID NO: 4170; (i-18) SEQ ID NO: 4180; (i-19) SEQ ID NO: 4190; (i-20) SEQ ID NO: 4200; (i-21) SEQ ID NO: 4210; (i-22) SEQ ID NO: 4220; (i- 23) SEQ ID NO: 4230; (i-24) SEQ ID NO: 4240; (i-25) SEQ ID NO: 4250; (i-26) SEQ ID NO: 4260; (i-27) SEQ ID NO: 4270; (i-28) SEQ ID NO: 4280; (i-29) SEQ ID NO: 4290; (i- 30) SEQ ID NO: 4300; (i-31) SEQ ID NO: 4310; (i-32) SEQ ID NO: 4320; (i-33) SEQ ID NO: 4330; (i-34) SEQ ID NO: 4340; (i-35) SEQ ID NO: 4350; (i-36) SEQ ID NO: 4360; (i- 37) SEQ ID NO: 4370; (i-38) SEQ ID NO: 4380; (i-39) SEQ ID NO: 4390; (i-40) SEQ ID NO: 4400; (i-41) SEQ ID NO: 4410; (i-42) SEQ ID NO: 4420; (i-43) SEQ ID NO: 4430; or (i-44) SEQ ID NO: 4440.

[0104] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (ii-1) SEQ ID NO: 5010; (ii-2) SEQ ID NO: 5020; (ii-3) SEQ ID NO: 5030; (ii-4) SEQ ID NO: 5040; (ii-5) SEQ ID NO: 5050; (ii-6) SEQ ID NO: 5060; (ii-7) SEQ ID NO: 5070; (ii-8) SEQ ID NO: 5080; (ii-9) SEQ ID NO: 5090; (ii-10) SEQ ID NO: 5100; (ii-11) SEQ ID NO: 5110; (ii-12) 32 Attorney Docket No.: 1160430.004613 SEQ ID NO: 5120; (ii-13) SEQ ID NO: 5130; (ii-14) SEQ ID NO: 5140; (ii-15) SEQ ID NO: 5150; (ii-16) SEQ ID NO: 5160; (ii-17) SEQ ID NO: 5170; (ii-18) SEQ ID NO: 5180; (ii-19) SEQ ID NO: 5190; (ii-20) SEQ ID NO: 5200; (ii-21) SEQ ID NO: 5210; (ii-22) SEQ ID NO: 5220; (ii-23) SEQ ID NO: 5230; (ii-24) SEQ ID NO: 5240; (ii-25) SEQ ID NO: 5250; (ii-26) SEQ ID NO: 5260; (ii-27) SEQ ID NO: 5270; (ii-28) SEQ ID NO: 5280; (ii-29) SEQ ID NO: 5290; (ii-30) SEQ ID NO: 5300; (ii-31) SEQ ID NO: 5310; (ii-32) SEQ ID NO: 5320; (ii-33) SEQ ID NO: 5330; or (ii-34) SEQ ID NO: 5340.

[0105] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (iii-1) SEQ ID NO: 6010; (iii-2) SEQ ID NO: 6020; (iii-3) SEQ ID NO: 6030; (iii-4) SEQ ID NO: 6040; (iii- 5) SEQ ID NO: 6050; (iii-6) SEQ ID NO: 6060; (iii-7) SEQ ID NO: 6070; (iii-8) SEQ ID NO: 6080; (iii-9) SEQ ID NO: 6090; (iii-10) SEQ ID NO: 6100; (iii-11) SEQ ID NO: 6110; (iii-12) SEQ ID NO: 6120; (iii-13) SEQ ID NO: 6130; (iii-14) SEQ ID NO: 6140; (iii-15) SEQ ID NO: 6150; (iii-16) SEQ ID NO: 6160; (iii-17) SEQ ID NO: 6170; (iii-18) SEQ ID NO: 6180; (iii-19) SEQ ID NO: 6190; (iii-20) SEQ ID NO: 6200; (iii-21) SEQ ID NO: 6210; (iii-22) SEQ ID NO: 6220; (iii-23) SEQ ID NO: 6230; (iii-24) SEQ ID NO: 6240; (iii-25) SEQ ID NO: 6250; (iii-26) SEQ ID NO: 6260; (iii-27) SEQ ID NO: 6270; (iii-28) SEQ ID NO: 6280; (iii-29) SEQ ID NO: 6290; (iii-30) SEQ ID NO: 6300; (iii-31) SEQ ID NO: 6310; (iii-32) SEQ ID NO: 6320; (iii-33) SEQ ID NO: 6330; (iii-34) SEQ ID NO: 6340; (iii-35) SEQ ID NO: 6350; (iii-36) SEQ ID NO: 6360; (iii-37) SEQ ID NO: 6370; (iii-38) SEQ ID NO: 6380; (iii-39) SEQ ID NO: 6390; (iii-40) SEQ ID NO: 6400; (iii-41) SEQ ID NO: 6410; (iii-42) SEQ ID NO: 6420; (iii-43) SEQ ID NO: 6430; (iii-44) SEQ ID NO: 6440; (iii-45) SEQ ID NO: 6450; (iii-46) SEQ ID NO: 6460; (iii-47) SEQ ID NO: 6470; or (iii-48) SEQ ID NO: 6480.

[0106] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (iv-1) SEQ ID NO: 7010; (iv-2) SEQ ID NO: 7020; (iv-3) SEQ ID NO: 7030; (iv-4) SEQ ID NO: 7040; (iv- 5) SEQ ID NO: 7050; (iv-6) SEQ ID NO: 7060; (iv-7) SEQ ID NO: 7070; (iv-8) SEQ ID NO: 7080; (iv-9) SEQ ID NO: 7090; (iv-10) SEQ ID NO: 7100; (iv-11) SEQ ID NO: 7110; (iv-12) SEQ ID NO: 7120; (iv-13) SEQ ID NO: 7130; (iv-14) SEQ ID NO: 7140; (iv-15) SEQ ID NO: 7150; (iv-16) SEQ ID NO: 7160; (iv-17) SEQ ID NO: 7170; (iv-18) SEQ ID 33 Attorney Docket No.: 1160430.004613 NO: 7180; (iv-19) SEQ ID NO: 7190; (iv-20) SEQ ID NO: 7200; (iv-21) SEQ ID NO: 7210; (iv-22) SEQ ID NO: 7220; (iv-23) SEQ ID NO: 7230; (iv-24) SEQ ID NO: 7240; (iv-25) SEQ ID NO: 7250; (iv-26) SEQ ID NO: 7260; (iv-27) SEQ ID NO: 7270; (iv-28) SEQ ID NO: 7280; or (iv-29) SEQ ID NO: 7290.

[0107] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (v-1) SEQ ID NO: 8010; (v-2) SEQ ID NO: 8020; (v-3) SEQ ID NO: 8030; (v-4) SEQ ID NO: 8040; (v-5) SEQ ID NO: 8050; (v-6) SEQ ID NO: 8060; (v-7) SEQ ID NO: 8070; (v-8) SEQ ID NO: 8080; (v-9) SEQ ID NO: 8090; (v-10) SEQ ID NO: 8100; (v-11) SEQ ID NO: 8110; (v-12) SEQ ID NO: 8120; (v-13) SEQ ID NO: 8130; (v-14) SEQ ID NO: 8140; (v-15) SEQ ID NO: 8150; (v-16) SEQ ID NO: 8160; (v-17) SEQ ID NO: 8170; (v-18) SEQ ID NO: 8180; (v-19) SEQ ID NO: 8190; (v-20) SEQ ID NO: 8200; (v-21) SEQ ID NO: 8210; (v-22) SEQ ID NO: 8220; (v-23) SEQ ID NO: 8230; (v-24) SEQ ID NO: 8240; (v-25) SEQ ID NO: 8250; (v-26) SEQ ID NO: 8260; (v-27) SEQ ID NO: 8270; (v-28) SEQ ID NO: 8280; (v-29) SEQ ID NO: 8290; (v-30) SEQ ID NO: 8300; (v-31) SEQ ID NO: 8310; or (v-32) SEQ ID NO: 8320.

[0108] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (vi-1) SEQ ID NO: 9010; (vi-2) SEQ ID NO: 9020; (vi-3) SEQ ID NO: 9030; (vi-4) SEQ ID NO: 9040; (vi- 5) SEQ ID NO: 9050; (vi-6) SEQ ID NO: 9060; (vi-7) SEQ ID NO: 9070; (vi-8) SEQ ID NO: 9080; (vi-9) SEQ ID NO: 9090; (vi-10) SEQ ID NO: 9100; (vi-11) SEQ ID NO: 9110; (vi-12) SEQ ID NO: 9120; (vi-13) SEQ ID NO: 9130; (vi-14) SEQ ID NO: 9140; (vi-15) SEQ ID NO: 9150; (vi-16) SEQ ID NO: 9160; (vi-17) SEQ ID NO: 9170; (vi-18) SEQ ID NO: 9180; (vi-19) SEQ ID NO: 9190; (vi-20) SEQ ID NO: 9200; (vi-21) SEQ ID NO: 9210; (vi-22) SEQ ID NO: 9220; (vi-23) SEQ ID NO: 9230; (vi-24) SEQ ID NO: 9240; (vi-25) SEQ ID NO: 9250; (vi-26) SEQ ID NO: 9260; (vi-27) SEQ ID NO: 9270; or (vi-28) SEQ ID NO: 9280.

[0109] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (i) SEQ ID NOS: 110; (ii) SEQ ID NO: 210; (iii) SEQ ID NO: 310; (iv) SEQ ID NO: 410; (v) SEQ ID NO: 510; (vi) SEQ ID NO: 610; (vii) SEQ ID NO: 710; (viii) SEQ ID NO: 810; (ix) SEQ ID 34 Attorney Docket No.: 1160430.004613 NO: 910; (x) SEQ ID NO: 1010; (xi) SEQ ID NO: 1110; (xii) SEQ ID NO: 1210; (xiii) SEQ ID NO: 1310; (xiv) SEQ ID NO: 1410; (xv) SEQ ID NO: 1510; (xvi) SEQ ID NO: 1610; (xvii) SEQ ID NO: 1710; (xviii) SEQ ID NO: 1810; (xix) SEQ ID NO: 1910; (xx) SEQ ID NO: 2010; (xxi) SEQ ID NO: 2110; (xxii) SEQ ID NO: 2210; (xxiii) SEQ ID NO: 2310; (xxiv) SEQ ID NO: 2410; (xxv) SEQ ID NO: 2510; (xxvi) SEQ ID NO: 2610; (xxvii) SEQ ID NO: 2710; (xxviii) SEQ ID NO: 2810; (xxix) SEQ ID NO: 2910; or (xxx) SEQ ID NO: 3010, except that the VH-1 comprises at least one of said one or more amino acid modifications or one or more amino acids. In some cases, the VH-1 may comprise one or more of F or Y at position 37, E at position 44, and / or R at position 45, wherein the position is according to Kabat or Martin numbering. In particular cases, the VH-1 may comprise F or Y at position 37, E at position 44, and R at position 45, wherein the position is according to Kabat or Martin numbering.

[0110] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (xxxi) SEQ ID NOS: 10110; (xxxii) SEQ ID NO: 10210; (xxxiii) SEQ ID NO: 10310; (xxxiv) SEQ ID NO: 10410; (xxxv) SEQ ID NO: 10510; (xxxvi) SEQ ID NO: 10610; (xxxvii) SEQ ID NO: 10710; (xxxviii) SEQ ID NO: 10810; (xxxix) SEQ ID NO: 10910; (xl) SEQ ID NO: 11010; (xli) SEQ ID NO: 11110; (xlii) SEQ ID NO: 11210; (xliii) SEQ ID NO: 11310; (xliv) SEQ ID NO: 11410; (xlv) SEQ ID NO: 11510; (xlvi) SEQ ID NO: 11610; (xlvii) SEQ ID NO: 11710; or (xlviii) SEQ ID NO: 11810, except that the VH-1 comprises at least one of said one or more amino acid modifications or one or more amino acids. In some cases, the VH-1 may comprise one or more of F or Y at position 37, E at position 44, and / or R at position 45, wherein the position is according to Kabat or Martin numbering. In particular cases, the VH-1 may comprise F or Y at position 37, E at position 44, and R at position 45, wherein the position is according to Kabat or Martin numbering.

[0111] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may, respectively, comprise or consist of: the FR1 amino acid sequence of SEQ ID NO: 3901, wherein X1 is E or Q, X2 is V or L, X3 is E or Q, X4 is G or A, X5 is G or E, X6 is L or V, X7 is V or K, X8 is Q or K, X9 is G, R, or S, X10 is L or V, X11 is R or K, X12 is L or V, X13 is A, K, or S, and X14 is G or A; the FR2 amino acid sequence of SEQ ID NO: 3903, wherein X1 is Y, V, or F, X2 is K or Q, X3 is Q or E, X4 is E or D, X5 is L, W, or F, X6 is V or M, and X7 is A, S, or G; the FR3 amino acid sequence of 35 Attorney Docket No.: 1160430.004613 SEQ ID NO: 3905, wherein X1 is F or V, X2 is S or T, X3 is R or A, X4 is N or E, X5 is A, S, or V, X6 is Q, K, T, or R, X7 is N, S, T, or K, X8 is S or T, X9 is V, L, or A, X10 is L or M, X11 is Q or E, X12 is M or L, X13 is N or S, X14 is R or K, X15 is A, S, or P, X16 is V or L, and X17 is F or Y; and the FR4 amino acid sequence of SEQ ID NO: 3907, wherein X1 is Q or R.

[0112] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences of: (i-1) SEQ ID NOS: 4011, 4013, 4015, and 4017, respectively; (i-2) SEQ ID NOS: 4021, 4023, 4025, and 4027, respectively; (i-3) SEQ ID NOS: 4031, 4033, 4035, and 4037, respectively; (i-4) SEQ ID NOS: 4041, 4043, 4045, and 4047, respectively; (i-5) SEQ ID NOS: 4051, 4053, 4055, and 4057, respectively; (i-6) SEQ ID NOS: 4061, 4063, 4065, and 4067, respectively; (i-7) SEQ ID NOS: 4071, 4073, 4075, and 4077, respectively; (i-8) SEQ ID NOS: 4081, 4083, 4085, and 4087, respectively; (i-9) SEQ ID NOS: 4091, 4093, 4095, and 4097, respectively; (i-10) SEQ ID NOS: 4101, 4103, 4105, and 4107, respectively; (i-11) SEQ ID NOS: 4111, 4113, 4115, and 4117, respectively; (i-12) SEQ ID NOS: 4121, 4123, 4125, and 4127, respectively; (i-13) SEQ ID NOS: 4131, 4133, 4135, and 4137, respectively; (i-14) SEQ ID NOS: 4141, 4143, 4145, and 4147, respectively; (i-15) SEQ ID NOS: 4151, 4153, 4155, and 4157, respectively; (i-16) SEQ ID NOS: 4161, 4163, 4165, and 4167, respectively; (i-17) SEQ ID NOS: 4171, 4173, 4175, and 4177, respectively; (i-18) SEQ ID NOS: 4181, 4183, 4185, and 4187, respectively; (i-19) SEQ ID NOS: 4191, 4193, 4195, and 4197, respectively; (i-20) SEQ ID NOS: 4201, 4203, 4205, and 4207, respectively; (i-21) SEQ ID NOS: 4211, 4213, 4215, and 4217, respectively; (i-22) SEQ ID NOS: 4221, 4223, 4225, and 4227, respectively; (i-23) SEQ ID NOS: 4231, 4233, 4235, and 4237, respectively; (i-24) SEQ ID NOS: 4241, 4243, 4245, and 4247, respectively; (i-25) SEQ ID NOS: 4251, 4253, 4255, and 4257, respectively; (i-26) SEQ ID NOS: 4261, 4263, 4265, and 4267, respectively; (i-27) SEQ ID NOS: 4271, 4273, 4275, and 4277, respectively; (i-28) SEQ ID NOS: 4281, 4283, 4285, and 4287, respectively; (i-29) SEQ ID NOS: 4291, 4293, 4295, and 4297, respectively; (i-30) SEQ ID NOS: 4301, 4303, 4305, and 4307, respectively; (i-31) SEQ ID NOS: 4311, 4313, 4315, and 4317, respectively; (i-32) SEQ ID NOS: 4321, 4323, 4325, and 4327, respectively; (i-33) SEQ ID NOS: 4331, 4333, 4335, and 4337, respectively; (i-34) SEQ ID NOS: 4341, 4343, 4345, and 4347, respectively; (i-35) SEQ ID NOS: 4351, 4353, 4355, and 4357, respectively; (i-36) SEQ ID NOS: 4361, 4363, 4365, and 4367, respectively; (i-37) SEQ ID NOS: 4371, 4373, 4375, and 4377, respectively; 36 Attorney Docket No.: 1160430.004613 (i-38) SEQ ID NOS: 4381, 4383, 4385, and 4387, respectively; (i-39) SEQ ID NOS: 4391, 4393, 4395, and 4397, respectively; (i-40) SEQ ID NOS: 4401, 4403, 4405, and 4407, respectively; (i-41) SEQ ID NOS: 4411, 4413, 4415, and 4417, respectively; (i-42) SEQ ID NOS: 4421, 4423, 4425, and 4427, respectively; (i-43) SEQ ID NOS: 4431, 4433, 4435, and 4437, respectively; or (i-44) SEQ ID NOS: 4441, 4443, 4445, and 4447, respectively.

[0113] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences of: (ii-1) SEQ ID NOS: 5011, 5013, 5015, and 5017, respectively; (ii-2) SEQ ID NOS: 5021, 5023, 5025, and 5027, respectively; (ii-3) SEQ ID NOS: 5031, 5033, 5035, and 5037, respectively; (ii-4) SEQ ID NOS: 5041, 5043, 5045, and 5047, respectively; (ii-5) SEQ ID NOS: 5051, 5053, 5055, and 5057, respectively; (ii-6) SEQ ID NOS: 5061, 5063, 5065, and 5067, respectively; (ii-7) SEQ ID NOS: 5071, 5073, 5075, and 5077, respectively; (ii-8) SEQ ID NOS: 5081, 5083, 5085, and 5087, respectively; (ii-9) SEQ ID NOS: 5091, 5093, 5095, and 5097, respectively; (ii-10) SEQ ID NOS: 5101, 5103, 5105, and 5107, respectively; (ii-11) SEQ ID NOS: 5111, 5113, 5115, and 5117, respectively; (ii-12) SEQ ID NOS: 5121, 5123, 5125, and 5127, respectively; (ii-13) SEQ ID NOS: 5131, 5133, 5135, and 5137, respectively; (ii-14) SEQ ID NOS: 5141, 5143, 5145, and 5147, respectively; (ii-15) SEQ ID NOS: 5151, 5153, 5155, and 5157, respectively; (ii-16) SEQ ID NOS: 5161, 5163, 5165, and 5167, respectively; (ii-17) SEQ ID NOS: 5171, 5173, 5175, and 5177, respectively; (ii-18) SEQ ID NOS: 5181, 5183, 5185, and 5187, respectively; (ii-19) SEQ ID NOS: 5191, 5193, 5195, and 5197, respectively; (ii-20) SEQ ID NOS: 5201, 5203, 5205, and 5207, respectively; (ii-21) SEQ ID NOS: 5211, 5213, 5215, and 5217, respectively; (ii-22) SEQ ID NOS: 5221, 5223, 5225, and 5227, respectively; (ii-23) SEQ ID NOS: 5231, 5233, 5235, and 5237, respectively; (ii-24) SEQ ID NOS: 5241, 5243, 5245, and 5247, respectively; (ii-25) SEQ ID NOS: 5251, 5253, 5255, and 5257, respectively; (ii-26) SEQ ID NOS: 5261, 5263, 5265, and 5267, respectively; (ii-27) SEQ ID NOS: 5271, 5273, 5275, and 5277, respectively; (ii-28) SEQ ID NOS: 5281, 5283, 5285, and 5287, respectively; (ii-29) SEQ ID NOS: 5291, 5293, 5295, and 5297, respectively; (ii-30) SEQ ID NOS: 5301, 5303, 5305, and 5307, respectively; (ii-31) SEQ ID NOS: 5311, 5313, 5315, and 5317, respectively; (ii-32) SEQ ID NOS: 5321, 5323, 5325, and 5327, respectively; (ii-33) SEQ ID NOS: 5331, 5333, 5335, and 5337, respectively; or (ii-34) SEQ ID NOS: 5341, 5343, 5345, and 5347, respectively. 37 Attorney Docket No.: 1160430.004613

[0114] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences of: (iii-1) SEQ ID NOS: 6011, 6013, 6015, and 6017, respectively; (iii-2) SEQ ID NOS: 6021, 6023, 6025, and 6027, respectively; (iii-3) SEQ ID NOS: 6031, 6033, 6035, and 6037, respectively; (iii-4) SEQ ID NOS: 6041, 6043, 6045, and 6047, respectively; (iii-5) SEQ ID NOS: 6051, 6053, 6055, and 6057, respectively; (iii-6) SEQ ID NOS: 6061, 6063, 6065, and 6067, respectively; (iii-7) SEQ ID NOS: 6071, 6073, 6075, and 6077, respectively; (iii-8) SEQ ID NOS: 6081, 6083, 6085, and 6087, respectively; (iii-9) SEQ ID NOS: 6091, 6093, 6095, and 6097, respectively; (iii-10) SEQ ID NOS: 6101, 6103, 6105, and 6107, respectively; (iii-11) SEQ ID NOS: 6111, 6113, 6115, and 6117, respectively; (iii-12) SEQ ID NOS: 6121, 6123, 6125, and 6127, respectively; (iii-13) SEQ ID NOS: 6131, 6133, 6135, and 6137, respectively; (iii-14) SEQ ID NOS: 6141, 6143, 6145, and 6147, respectively; (iii-15) SEQ ID NOS: 6151, 6153, 6155, and 6157, respectively; (iii-16) SEQ ID NOS: 6161, 6163, 6165, and 6167, respectively; (iii-17) SEQ ID NOS: 6171, 6173, 6175, and 6177, respectively; (iii-18) SEQ ID NOS: 6181, 6183, 6185, and 6187, respectively; (iii- 19) SEQ ID NOS: 6191, 6193, 6195, and 6197, respectively; (iii-20) SEQ ID NOS: 6201, 6203, 6205, and 6207, respectively; (iii-21) SEQ ID NOS: 6211, 6213, 6215, and 6217, respectively; (iii-22) SEQ ID NOS: 6221, 6223, 6225, and 6227, respectively; (iii-23) SEQ ID NOS: 6231, 6233, 6235, and 6237, respectively; (iii-24) SEQ ID NOS: 6241, 6243, 6245, and 6247, respectively; (iii-25) SEQ ID NOS: 6251, 6253, 6255, and 6257, respectively; (iii- 26) SEQ ID NOS: 6261, 6263, 6265, and 6267, respectively; (iii-27) SEQ ID NOS: 6271, 6273, 6275, and 6277, respectively; (iii-28) SEQ ID NOS: 6281, 6283, 6285, and 6287, respectively; (iii-29) SEQ ID NOS: 6291, 6293, 6295, and 6297, respectively; (iii-30) SEQ ID NOS: 6301, 6303, 6305, and 6307, respectively; (iii-31) SEQ ID NOS: 6311, 6313, 6315, and 6317, respectively; (iii-32) SEQ ID NOS: 6321, 6323, 6325, and 6327, respectively; (iii- 33) SEQ ID NOS: 6331, 6333, 6335, and 6337, respectively; (iii-34) SEQ ID NOS: 6341, 6343, 6345, and 6347, respectively; (iii-35) SEQ ID NOS: 6351, 6353, 6355, and 6357, respectively; (iii-36) SEQ ID NOS: 6361, 6363, 6365, and 6367, respectively; (iii-37) SEQ ID NOS: 6371, 6373, 6375, and 6377, respectively; (iii-38) SEQ ID NOS: 6381, 6383, 6385, and 6387, respectively; (iii-39) SEQ ID NOS: 6391, 6393, 6395, and 6397, respectively; (iii- 40) SEQ ID NOS: 6401, 6403, 6405, and 6407, respectively; (iii-41) SEQ ID NOS: 6411, 6413, 6415, and 6417, respectively; (iii-42) SEQ ID NOS: 6421, 6423, 6425, and 6427, respectively; (iii-43) SEQ ID NOS: 6431, 6433, 6435, and 6437, respectively; (iii-44) SEQ ID NOS: 6441, 6443, 6445, and 6447, respectively; (iii-45) SEQ ID NOS: 6451, 6453, 6455, 38 Attorney Docket No.: 1160430.004613 and 6457, respectively; (iii-46) SEQ ID NOS: 6461, 6463, 6465, and 6467, respectively; (iii- 47) SEQ ID NOS: 6471, 6473, 6475, and 6477, respectively; or (iii-48) SEQ ID NOS: 6481, 6483, 6485, and 6487, respectively.

[0115] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences of: (iv-1) SEQ ID NOS: 7011, 7013, 7015, and 7017, respectively; (iv-2) SEQ ID NOS: 7021, 7023, 7025, and 7027, respectively; (iv-3) SEQ ID NOS: 7031, 7033, 7035, and 7037, respectively; (iv-4) SEQ ID NOS: 7041, 7043, 7045, and 7047, respectively; (iv-5) SEQ ID NOS: 7051, 7053, 7055, and 7057, respectively; (iv-6) SEQ ID NOS: 7061, 7063, 7065, and 7067, respectively; (iv-7) SEQ ID NOS: 7071, 7073, 7075, and 7077, respectively; (iv-8) SEQ ID NOS: 7081, 7083, 7085, and 7087, respectively; (iv-9) SEQ ID NOS: 7091, 7093, 7095, and 7097, respectively; (iv-10) SEQ ID NOS: 7101, 7103, 7105, and 7107, respectively; (iv-11) SEQ ID NOS: 7111, 7113, 7115, and 7117, respectively; (iv-12) SEQ ID NOS: 7121, 7123, 7125, and 7127, respectively; (iv-13) SEQ ID NOS: 7131, 7133, 7135, and 7137, respectively; (iv-14) SEQ ID NOS: 7141, 7143, 7145, and 7147, respectively; (iv- 15) SEQ ID NOS: 7151, 7153, 7155, and 7157, respectively; (iv-16) SEQ ID NOS: 7161, 7163, 7165, and 7167, respectively; (iv-17) SEQ ID NOS: 7171, 7173, 7175, and 7177, respectively; (iv-18) SEQ ID NOS: 7181, 7183, 7185, and 7187, respectively; (iv-19) SEQ ID NOS: 7191, 7193, 7195, and 7197, respectively; (iv-20) SEQ ID NOS: 7201, 7203, 7205, and 7207, respectively; (iv-21) SEQ ID NOS: 7211, 7213, 7215, and 7217, respectively; (iv- 22) SEQ ID NOS: 7221, 7223, 7225, and 7227, respectively; (iv-23) SEQ ID NOS: 7231, 7233, 7235, and 7237, respectively; (iv-24) SEQ ID NOS: 7241, 7243, 7245, and 7247, respectively; (iv-25) SEQ ID NOS: 7251, 7253, 7255, and 7257, respectively; (iv-26) SEQ ID NOS: 7261, 7263, 7265, and 7267, respectively; (iv-27) SEQ ID NOS: 7271, 7273, 7275, and 7277, respectively; (iv-28) SEQ ID NOS: 7281, 7283, 7285, and 7287, respectively; or (iv-29) SEQ ID NOS: 7291, 7293, 7295, and 7297, respectively.

[0116] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences of: (v-1) SEQ ID NOS: 8011, 8013, 8015, and 8017, respectively; (v-2) SEQ ID NOS: 8021, 8023, 8025, and 8027, respectively; (v-3) SEQ ID NOS: 8031, 8033, 8035, and 8037, respectively; (v-4) SEQ ID NOS: 8041, 8043, 8045, and 8047, respectively; (v-5) SEQ ID NOS: 8051, 8053, 8055, and 8057, respectively; (v-6) SEQ ID NOS: 8061, 8063, 8065, and 8067, respectively; (v-7) SEQ ID NOS: 8071, 8073, 8075, and 8077, respectively; 39 Attorney Docket No.: 1160430.004613 (v-8) SEQ ID NOS: 8081, 8083, 8085, and 8087, respectively; (v-9) SEQ ID NOS: 8091, 8093, 8095, and 8097, respectively; (v-10) SEQ ID NOS: 8101, 8103, 8105, and 8107, respectively; (v-11) SEQ ID NOS: 8111, 8113, 8115, and 8117, respectively; (v-12) SEQ ID NOS: 8121, 8123, 8125, and 8127, respectively; (v-13) SEQ ID NOS: 8131, 8133, 8135, and 8137, respectively; (v-14) SEQ ID NOS: 8141, 8143, 8145, and 8147, respectively; (v-15) SEQ ID NOS: 8151, 8153, 8155, and 8157, respectively; (v-16) SEQ ID NOS: 8161, 8163, 8165, and 8167, respectively; (v-17) SEQ ID NOS: 8171, 8173, 8175, and 8177, respectively; (v-18) SEQ ID NOS: 8181, 8183, 8185, and 8187, respectively; (v-19) SEQ ID NOS: 8191, 8193, 8195, and 8197, respectively; (v-20) SEQ ID NOS: 8201, 8203, 8205, and 8207, respectively; (v-21) SEQ ID NOS: 8211, 8213, 8215, and 8217, respectively; (v-22) SEQ ID NOS: 8221, 8223, 8225, and 8227, respectively; (v-23) SEQ ID NOS: 8231, 8233, 8235, and 8237, respectively; (v-24) SEQ ID NOS: 8241, 8243, 8245, and 8247, respectively; (v-25) SEQ ID NOS: 8251, 8253, 8255, and 8257, respectively; (v-26) SEQ ID NOS: 8261, 8263, 8265, and 8267, respectively; (v-27) SEQ ID NOS: 8271, 8273, 8275, and 8277, respectively; (v-28) SEQ ID NOS: 8281, 8283, 8285, and 8287, respectively; (v-29) SEQ ID NOS: 8291, 8293, 8295, and 8297, respectively; (v-30) SEQ ID NOS: 8301, 8303, 8305, and 8307, respectively; (v-31) SEQ ID NOS: 8311, 8313, 8315, and 8317, respectively; or (v-32) SEQ ID NOS: 8321, 8323, 8325, and 8327, respectively.

[0117] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences of: (vi-1) SEQ ID NOS: 9011, 9013, 9015, and 9017, respectively; (vi-2) SEQ ID NOS: 9021, 9023, 9025, and 9027, respectively; (vi-3) SEQ ID NOS: 9031, 9033, 9035, and 9037, respectively; (vi-4) SEQ ID NOS: 9041, 9043, 9045, and 9047, respectively; (vi-5) SEQ ID NOS: 9051, 9053, 9055, and 9057, respectively; (vi-6) SEQ ID NOS: 9061, 9063, 9065, and 9067, respectively; (vi-7) SEQ ID NOS: 9071, 9073, 9075, and 9077, respectively; (vi-8) SEQ ID NOS: 9081, 9083, 9085, and 9087, respectively; (vi-9) SEQ ID NOS: 9091, 9093, 9095, and 9097, respectively; (vi-10) SEQ ID NOS: 9101, 9103, 9105, and 9107, respectively; (vi-11) SEQ ID NOS: 9111, 9113, 9115, and 9117, respectively; (vi-12) SEQ ID NOS: 9121, 9123, 9125, and 9127, respectively; (vi-13) SEQ ID NOS: 9131, 9133, 9135, and 9137, respectively; (vi-14) SEQ ID NOS: 9141, 9143, 9145, and 9147, respectively; (vi- 15) SEQ ID NOS: 9151, 9153, 9155, and 9157, respectively; (vi-16) SEQ ID NOS: 9161, 9163, 9165, and 9167, respectively; (vi-17) SEQ ID NOS: 9171, 9173, 9175, and 9177, respectively; (vi-18) SEQ ID NOS: 9181, 9183, 9185, and 9187, respectively; (vi-19) SEQ 40 Attorney Docket No.: 1160430.004613 ID NOS: 9191, 9193, 9195, and 9197, respectively; (vi-20) SEQ ID NOS: 9201, 9203, 9205, and 9207, respectively; (vi-21) SEQ ID NOS: 9211, 9213, 9215, and 9217, respectively; (vi- 22) SEQ ID NOS: 9221, 9223, 9225, and 9227, respectively; (vi-23) SEQ ID NOS: 9231, 9233, 9235, and 9237, respectively; (vi-24) SEQ ID NOS: 9241, 9243, 9245, and 9247, respectively; (vi-25) SEQ ID NOS: 9251, 9253, 9255, and 9257, respectively; (vi-26) SEQ ID NOS: 9261, 9263, 9265, and 9267, respectively; (vi-27) SEQ ID NOS: 9271, 9273, 9275, and 9277, respectively; or (vi-28) SEQ ID NOS: 9281, 9283, 9285, and 9287, respectively.

[0118] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences of: (i) SEQ ID NOS: 111, 113, 115, and 117, respectively; (ii) SEQ ID NOS: 211, 213, 215, and 217, respectively; (iii) SEQ ID NOS: 311, 313, 315, and 317, respectively; (iv) SEQ ID NOS: 411, 413, 415, and 417, respectively; (v) SEQ ID NOS: 511, 513, 515, and 517, respectively; (vi) SEQ ID NOS: 611, 613, 615, and 617, respectively; (vii) SEQ ID NOS: 711, 713, 715, and 717, respectively; (viii) SEQ ID NOS: 811, 813, 815, and 817, respectively; (ix) SEQ ID NOS: 911, 913, 915, and 917, respectively; (x) SEQ ID NOS: 1011, 1013, 1015, and 1017, respectively; (xi) SEQ ID NOS: 1111, 1113, 1115, and 1117, respectively; (xii) SEQ ID NOS: 1211, 1213, 1215, and 1217, respectively; (xiii) SEQ ID NOS: 1311, 1313, 1315, and 1317, respectively; (xiv) SEQ ID NOS: 1411, 1413, 1415, and 1417, respectively; (xv) SEQ ID NOS: 1511, 1513, 1515, and 1517, respectively; (xvi) SEQ ID NOS: 1611, 1613, 1615, and 1617, respectively; (xvii) SEQ ID NOS: 1711, 1713, 1715, and 1717, respectively; (xviii) SEQ ID NOS: 1811, 1813, 1815, and 1817, respectively; (xix) SEQ ID NOS: 1911, 1913, 1915, and 1917, respectively; (xx) SEQ ID NOS: 2011, 2013, 2015, and 2017, respectively; (xxi) SEQ ID NOS: 2111, 2113, 2115, and 2117, respectively; (xxii) SEQ ID NOS: 2211, 2213, 2215, and 2217, respectively; (xxiii) SEQ ID NOS: 2311, 2313, 2315, and 2317, respectively; (xxiv) SEQ ID NOS: 2411, 2413, 2415, and 2417, respectively; (xxv) SEQ ID NOS: 2511, 2513, 2515, and 2517, respectively; (xxvi) SEQ ID NOS: 2611, 2613, 2615, and 2617, respectively; (xxvii) SEQ ID NOS: 2711, 2713, 2715, and 2717, respectively; (xxviii) SEQ ID NOS: 2811, 2813, 2815, and 2817, respectively; (xxix) SEQ ID NOS: 2911, 2913, 2915, and 2917, respectively; or (xxx) SEQ ID NOS: 3011, 3013, 3015, and 3017, respectively, except that the VH-1 comprises at least one of said one or more amino acid modifications or one or more amino acids. In some cases, the VH-1 may comprise one or more of F or Y at position 37, E at position 44, and / or R at position 45, wherein the position is according to Kabat or Martin numbering. In particular cases, the VH-1 may 41 Attorney Docket No.: 1160430.004613 comprise F or Y at position 37, E at position 44, and R at position 45, wherein the position is according to Kabat or Martin numbering.

[0119] In particular embodiments, the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 may comprise or consist of the FR1, FR2, FR3, and FR4 amino acid sequences of: (xxxi) SEQ ID NOS: 10111, 10113, 10115, and 10117, respectively; (xxxii) SEQ ID NOS: 10211, 10213, 10215, and 10217, respectively; (xxxiii) SEQ ID NOS: 10311, 10313, 10315, and 10317, respectively; (xxxiv) SEQ ID NOS: 10411, 10413, 10415, and 10417, respectively; (xxxv) SEQ ID NOS: 10511, 10513, 10515, and 10517, respectively; (xxxvi) SEQ ID NOS: 10611, 10613, 10615, and 10617, respectively; (xxxvii) SEQ ID NOS: 10711, 10713, 10715, and 10717, respectively; (xxxviii) SEQ ID NOS: 10811, 10813, 10815, and 10817, respectively; (xxxix) SEQ ID NOS: 10911, 10913, 10915, and 10917, respectively; (xl) SEQ ID NOS: 11011, 11013, 11015, and 11017, respectively; (xli) SEQ ID NOS: 11111, 11113, 11115, and 11117, respectively; (xlii) SEQ ID NOS: 11211, 11213, 11215, and 11217, respectively; (xliii) SEQ ID NOS: 11311, 11313, 11315, and 11317, respectively; (xliv) SEQ ID NOS: 11411, 11413, 11415, and 11417, respectively; (xlv) SEQ ID NOS: 11511, 11513, 11515, and 11517, respectively; (xlvi) SEQ ID NOS: 11611, 11613, 11615, and 11617, respectively; (xlvii) SEQ ID NOS: 11711, 11713, 11715, and 11717, respectively; or (xlviii) SEQ ID NOS: 11811, 11813, 11815, and 11817, respectively, except that the VH-1 comprises at least one of said one or more amino acid modifications or one or more amino acids. In some cases, the VH-1 may comprise one or more of F or Y at position 37, E at position 44, and / or R at position 45, wherein the position is according to Kabat or Martin numbering. In particular cases, the VH-1 may comprise F or Y at position 37, E at position 44, and R at position 45, wherein the position is according to Kabat or Martin numbering.

[0120] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment may comprise: (a) a heavy chain-only antibody (HCAb) format, a nanobody-Fc format, a nanobody-CH format, a single chain nanobody-CH format, a camel Ig format, and / or an IgNAR format, or a single-chain variant of any of the foregoing; (b) a single domain antibody (sdAb) format, a nanobody format, a tandem nanobody format; and / or (c) a format depicted in any of FIGS.1A, 1C (top or second from top), and 1D (top left, bottom left, top right or second top on the right).

[0121] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment may comprise or consist of: (a) a HCAb comprising the VH-1, a nanobody-Fc 42 Attorney Docket No.: 1160430.004613 comprising the VH-1, a nanobody-CH comprising the VH-1, a camel Ig comprising the VH- 1, an IgNAR comprising the VH-1, and / or a single-chain variant of any of the foregoing; (b) a sdAb comprising the VH-1; a nanobody comprising the VH-1; and / or a tandem nanobody comprising the VH-1; and / or (c) the antibody structure depicted in any of FIGS.1A, 1C (top or second from top), and 1D (top left, bottom left, top right or second top on the right) comprising the VH-1.

[0122] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment may further comprises a first light chain variable domain (VL-1) comprising: (a) a first light chain CDR1 (CDRL1-1); (b) a first light chain CDR2 (CDRH2-1); and (c) a first heavy chain CDR3 (CDRH3-1).

[0123] In certain embodiments, such an anti-human CD3 antibody or antigen-binding antibody fragment may comprise: (a) an immunoglobulin (Ig) format, optionally an IgG, IgA, IgE, IgD, or IgM format, further optionally an IgG1, IgG2, IgG3, or IgG4 format, or a half antibody variant of any of the foregoing; (b) an antibody fragment antigen-binding region (Fab) format, a Fab’ format, a F(ab’)2 format, a F(ab’)3 format, and / or a variable fragment (Fv) format; (c) a single chain fragment variable region (scFv) format, a tandem scFv format, a diabody format, a triabody format, a tetrabody format, a scFv-Fc format, a scFv-CH format, a minibody format, a scFv-zipper format, a diabody-Fc format, a diabody-CH format, a half antibody variant of any of the foregoing, and / or a single chain Fab (scFab) format; and / or (d) a format depicted in any of FIGS.1B, 1C (third from the top or the bottom), and 1D (top center, bottom center, third from the top on the right, or the right bottom).

[0124] In certain embodiments, such an anti-human CD3 antibody or antigen-binding antibody fragment may comprise or consist of: (a) a heavy chain comprising the VH-1 and a light chain comprising the VL-1, optionally wherein the anti-human CD3 antibody or antigen-binding antibody fragment: (a-1) consists of said heavy and light chains; (a-2) comprises or consists of an Ig molecule comprising two said heavy chains and two said light chains, or a multimer of said Ig molecule; and / or (a-3) comprises or consists of an IgG, IgA, IgE, IgD, or IgM, optionally an IgG1, IgG2, IgG3, or IgG4; and / or (b) a Fab comprising the VH-1 and the VL-1, a Fab’ comprising the VH-1 and the VL-1, a F(ab’)2 comprising the VH- 1 and the VL-1, a F(ab’)3comprising the VH-1 and the VL-1, and / or a Fv comprising the VH-1 and the VL-1; and / or (c) a scFv comprising the VH-1 and the VL-1, a tandem scFv comprising the VH-1 and the VL-1, a diabody comprising the VH-1 and the VL-1, a triabody comprising the VH-1 and the VL-1, a tetrabody comprising the VH-1 and the VL-1, a scFv- 43 Attorney Docket No.: 1160430.004613 Fc comprising the VH-1 and the VL-1, a scFv-CH comprising the VH-1 and the VL-1, a minibody comprising the VH-1 and the VL-1, a scFv-zipper comprising the VH-1 and the VL-1, a diabody-Fc comprising the VH-1 and the VL-1, a diabody-CH comprising the VH-1 and the VL-1, and / or a scFab comprising the VH-1 and the VL-1; and / or (d) an antibody structure depicted in any of FIGS.1B, 1C (third from the top or the bottom), and 1D (top center, bottom center, third from the top on the right, or the right bottom) comprising the VH-1 and the VL-1.

[0125] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may bind to cynomolgus CD3 and / or mouse CD3. In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may not bind to cynomolgus CD3. In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may not bind to mouse CD3.

[0126] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may bind to human CD3 with a KDof < about 1 μM, < about 500 nM, < about 200 nM, < about 100 nM, < about 50 nM, < about 20 nM, < about 10 nM, < about 5 nM, < about 2 nM, < about 1 nM, < about 500 pM, about 1 μM, about 500 nM, about 200 nM, about 100 nM, about 50 nM, about 20 nM, about 10 nM, about 5 nM, about 2 nM, about 1 nM, about 500 pM, about 200 pM, between about 100 nM and 1 nM, between about 50 nM and 1 nM, between about 20 nM and 1 nM, between about 10 nM and 1 nM, between about 5 nM and 1 nM, between about 2 nM and 1 nM, between about 10 nM and 500 pM, between about 5 nM and 500 pM, between about 2 nM and 500 pM, between about 1nM and 500 pM, between about 1 nM and 200 pM, or between about 500 pM and about 200 pM, at a physiological pH or at pH 7.4, optionally as measured by surface plasmon resonance (SPR) or bio-layer interferometry (BLI), further optionally as performed in Example 3.

[0127] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may bind to human CD3 with a KDof < about 1 μM, < about 500 nM, < about 200 nM, < about 100 nM, < about 50 nM, < about 20 nM, < about 10 nM, < about 5 nM, < about 2 nM, < about 1 nM, about 1 μM, about 500 nM, about 200 nM, about 100 nM, about 50 nM, about 20 nM, about 10 nM, about 5 nM, about 2 nM, or about 1 nM, at an acidic pH or at pH 6.0, optionally as measured by BLI, further optionally as performed in Example 3. 44 Attorney Docket No.: 1160430.004613

[0128] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may bind to human CD3 with a lower KDat an acidic pH or at pH 6.0 compared to at a physiological pH or at pH 7.4, optionally by or at least by about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8- fold, about 9-fold, about 10-fold, about 12-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900- fold, or about 1000-fold, optionally as measured by SPR or BLI, further optionally as performed in Example 3.

[0129] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may bind to human CD3 at an acidic pH or at pH 6.0 but does not bind to human CD3 at a physiological pH or at pH 7.4, optionally as measured by SPR or BLI, further optionally as performed in Example 3.

[0130] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may not bind to mouse or murine CD3 or binds to mouse or murine CD3 with a KDof > about 10 nM, > about 20 nM, > about 50 nM, > about 100 nM, > about 200 nM, > about 500 nM, > about 1 μM, about 10 nM, about 20 nM, about 50 nM, about 100 nM, about 200 nM, about 500 nM, or about 1 μM, optionally as measured by SPR or BLI, further optionally as performed in Example 3.

[0131] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may not bind to human CD3 monomer or binds to human CD3 monomer with a KDof > about 1 nM, > about 10 nM, > about 20 nM, > about 50 nM, > about 100 nM, > about 200 nM, > about 500 nM, > about 1 μM, about 1 nM, about 10 nM, about 20 nM, about 50 nM, about 100 nM, about 200 nM, about 500 nM, or about 1 μM, optionally as measured by SPR or BLI, further optionally as performed in Example 3.

[0132] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may compete with CTL-70330 (ADI-70330 in WO2023044402), CTL- 96829 (UCHT1 IgG), CTL-62223 (the anti-CD3 arm of mosunetuzumab), or does not compete with any of CTL-70330, CTL-96829, or CTL-62223, optionally as measured by SPR or BLI, further optionally as performed in Example 4. 45 Attorney Docket No.: 1160430.004613

[0133] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may bind to human CD3 expressing cells, optionally Jurkat cells, cynomolgus HSC-F cells, and / or human CD3-CHO cells, more efficiently compared to one or more of CTL-70330, CTL-96829, or CTL-62223, optionally as measured by flow cytometry, further optionally based on median or median fluorescence intensity and / or normalized cell binding (NCB) values, yet further optionally as performed in Example 5.

[0134] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may display a polyspecificity reagent (PSR) score of: score < 0.1 (clean); 0.10 ≤ score < 0.33 (low), or 0.33 ≤ score < 0.66 (medium), or 0.00 as measured by an PSR assay, optionally as performed in Example 6.

[0135] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may display a hydrophobic interaction chromatography (HIC) retention time (RT) of: RT < 9.5 minutes, RT < 10.0 minutes, or RT < 10.5 minutes (clean or low), or 10.5 minutes ≤ RT < 11.5 minutes (medium), as measured by HIC, optionally as performed in Examples.

[0136] In some embodiments, the anti-human CD3 antibody or antigen-binding antibody fragment thereof may display a melting temperature (Tm) of < about 45 ℃, < about 50 ℃, < about 55 ℃, < about 60 ℃, < about 65 ℃, < about 70 ℃, < about 75 ℃, < about 80 ℃, < about 85 ℃, > about 45 ℃, > about 50 ℃, > about 55 ℃, > about 60 ℃, > about 65 ℃, > about 70 ℃, > about 75 ℃, > about 80 ℃, > about 85 ℃, about 45 ℃, about 50 ℃, about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, or about 85 ℃, optionally as measured by differential scanning fluorimetry (DSF), further optionally as performed in Examples.

[0137] In some embodiments, an anti-human CD3 antibody or antigen-binding antibody fragment thereof according to the present disclosure may be capable of stimulating a T cell.

[0138] In certain embodiments, the stimulation of T cell may be as determined by increased expression of CD69, optionally as measured by flow cytometry, further optionally based on an increased mean fluorescence intensity (MFI), yet further optionally by about 5%, by about 10%, about 15%, by about 20%, about 25%, by about 30%, about 35%, by about 40%, about 45%, by about 50%, about 55%, by about 60%, about 65%, by about 70%, about 75%, by about 80%, about 85%, by about 90%, about 95%, by about 100%, by about 150%, by about 46 Attorney Docket No.: 1160430.004613 200%, by about 250%, by about 300%, by about 350%, by about 400%, by about 450%, or by 500%.

[0139] In certain embodiments, the stimulation of T cell may be as determined by increased release of IL-2, optionally by or at least by about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 12-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, or about 50-fold, optionally as measured by an immuno-assay, optionally Enzyme-linked immunosorbent assay (ELISA), optionally by about 5%, by about 10%, about 15%, by about 20%, about 25%, by about 30%, about 35%, by about 40%, about 45%, by about 50%, about 55%, by about 60%, about 65%, by about 70%, about 75%, by about 80%, about 85%, by about 90%, about 95%, by about 100%, by about 150%, by about 200%, by about 250%, by about 300%, by about 350%, by about 400%, by about 450%, or by 500%.

[0140] In certain embodiments, the stimulation of T cell may be as determined by increased transcriptional activation upon incubation of a T cell with the anti-human CD3 antibody or antigen-binding antibody fragment and optionally with an anti-human cluster of differentiation 28 (CD28) antibody.

[0141] In some cases, any of such features may be compared with a control (e.g., not specific to CD3) antibody or antigen-binding antibody fragment or a reference anti-CD3 antibody (e.g., stimulatory anti-CD3 antibody) with or without an anti-CD28 antibody, further optionally as performed in Example 7.

[0142] In some embodiments, an anti-human CD3 antibody or antigen-binding antibody fragment thereof according to the present disclosure may not stimulate a T cell (e.g., upon binding to a T cell).

[0143] In certain embodiments, the absence of T cell activation or minimal activation of a T cell may be as determined by no or minimal increase in expression of CD69. In some cases, the no or minimal increase in expression of CD69 may be measured by flow cytometry, optionally based on an increased mean fluorescence intensity (MFI). In some cases, the minimal increase may be by about 5% or below, by about 10%, about 15% or below, by about 20% or below, about 25% or below, by about 30% or below, about 35% or below, by about 40% or below, about 45% or below, by about 50% or below, about 55% or below, by about 60% or below, about 65% or below, by about 70% or below, about 75% or below, by 47 Attorney Docket No.: 1160430.004613 about 80% or below, about 85% or below, by about 90% or below, about 95% or below, by about 100% or below, by about 150% or below, by about 200% or below, by about 250% or below, by about 300% or below, or by about 350% or below.

[0144] In certain embodiments, the absence of T cell activation or minimal activation of a T cell may be as determined by no or minimal increase in release of IL-2. In some cases, no or minimal increase in release of IL-2 may be determined by an immuno-assay, optionally Enzyme-linked immunosorbent assay (ELISA). In some cases, the minimal increase may be by about 1.05-fold or below, about 1.1-fold or below, about 1.15-fold or below, about 1.2- fold or below, about 1.5-fold or below, about 2-fold or below, about 3-fold or below, about 4- fold or below, about 5-fold or below, about 6-fold or below, or about 7-fold or below, by about 5% or below, by about 10% or below, about 15% or below, by about 20% or below, about 25% or below, by about 30% or below, about 35% or below, by about 40% or below, about 45% or below, by about 50% or below, about 55% or below, by about 60% or below, about 65% or below, by about 70% or below, about 75% or below, by about 80% or below, about 85% or below, by about 90% or below, about 95% or below, by about 100% or below, by about 150% or below, by about 200% or below, by about 250% or below, by about 300% or below, by about 350% or below, by about 400% or below, by about 450% or below, or by 500% or below.

[0145] In certain embodiments, the absence of T cell activation or minimal activation of a T cell may be as determined by no or minimal increase in transcriptional activation upon incubation of a T cell with the anti-human CD3 antibody or antigen-binding antibody fragment and optionally with an anti-human cluster of differentiation 28 (CD28) antibody.

[0146] In some cases, any of such features may be compared with a control (e.g., not specific to CD3) antibody or antigen-binding antibody fragment or a reference anti-CD3 antibody (e.g., stimulatory anti-CD3 antibody) with or without an anti-CD28 antibody, further optionally as performed in Example 21.

[0147] In some embodiments, an anti-human CD3 antibody or antigen-binding antibody fragment thereof according to the present disclosure may reverses, inhibit, or suppress T cell or T cell activation.

[0148] In certain embodiments, the reversal, inhibition, or suppression of T cell activation of a T cell may be determined by reduced expression of CD69. In some cases, the reduced expression of CD69 may be measured by flow cytometry, optionally based on an increased 48 Attorney Docket No.: 1160430.004613 mean fluorescence intensity (MFI). In some cases, the reduced expression of CD69 may be by about 5%, by about 10%, about 15%, by about 20%, about 25%, by about 30%, about 35%, by about 40%, about 45%, by about 50%, about 55%, by about 60%, about 65%, by about 70%, about 75%, by about 80%, about 85%, by about 90%, about 95%, or by about 100%.

[0149] In certain embodiments, the reversal, inhibition, or suppression of T cell activation of a T cell may be determined by reduced release of IL-2. In some cases, the reduced release of IL-2 may be measured by an immuno-assay, optionally Enzyme-linked immunosorbent assay (ELISA). In some cases, the reduced release of IL-2 may be by about 5%, by about 10%, about 15%, by about 20%, about 25%, by about 30%, about 35%, by about 40%, about 45%, by about 50%, about 55%, by about 60%, about 65%, by about 70%, about 75%, by about 80%, about 85%, by about 90%, about 95%, or by about 100%.

[0150] In certain embodiments, the reversal, inhibition, or suppression of T cell activation of a T cell may be determined by reduced transcriptional activation upon incubation of a T cell with the anti-human CD3 antibody or antigen-binding antibody fragment and optionally with an anti-human cluster of differentiation 28 (CD28) antibody.

[0151] In some cases, any of such features may be compared with a control (e.g., not specific to CD3) antibody or antigen-binding antibody fragment or a reference anti-CD3 antibody (e.g., stimulatory anti-CD3 antibody) with or without an anti-CD28 antibody, further optionally as performed in Example 21.

[0152] One aspect of the present disclosure provides multi-specific antibodies. The multi- specific antibodies may comprise (1) a first antigen-binding region (ABR-1) that binds human CD3; and (2) a second antigen-binding region (ABR-2) that binds a second antigen. The ABR-1 may comprise any of the anti-human CD3 antibodies and antigen-binding antibody fragments described above or herein. The ABR-2 may comprise a second heavy chain variable domain (VH-2) comprising a second heavy chain complementarity determining region (CDR) 1 (CDRH1-2), a second heavy chain CDR2 (CDRH2-2), and a second heavy chain CDR3 (CDRH3-2). The ABR-2 may optionally further comprise a second light chain variable domain (VL-2) comprising a second light chain CDR1 (CDRL1- 2), a second light chain CDR2 (CDRL2-2), and a second light chain CDR3 (CDRL3-2). The ABR-2 may comprise a T-cell receptor TCR) or a fragment of a TCR, such as a TCR α-chain variable domain (Vα) and / or a TCR β-chain variable domain (Vβ). The Vα may comprise 49 Attorney Docket No.: 1160430.004613 CDR1, 2, and 3 the Vβ may comprise CDR1, 2, and 3. The second antigen may optionally be the same as or different from human CD3.

[0153] In some embodiments, the multi-specific antibody may be bispecific, trispecific, or tetraspecific.

[0154] In some embodiments, the second antigen may be or may comprise: (a) CD28, optionally human CD28; (b) a cancer antigen, optionally a tumor-specific antigen (TSA) or a tumor-associated antigen (TAA), optionally CD20; (c) CD3, optionally human CD3; (d) any one of the antigens selected from those listed in Table 2; and / or (e) any one of the cancer antigens, optionally any one of the TSAs or any one of the TAAs, selected from those listed in Table 2. In some embodiments, the second antigen may be or may comprise: (f) a molecule of interest presented on a major histocompatibility complex (MHC). In certain embodiments, the molecule of interest comprises a cancer antigen, optionally any one of the TSAs or any one of the TAAs optionally selected from those listed in Table 2, or a fragment thereof. In certain embodiments, the MHC is a MHC class I molecule, optionally HLA-A, HLA-B, or HLA-C, further optionally HLA-A2. In particular embodiments, the second antigen is or comprises gp100 presented on MHC class I, optionally HLA-A, further optionally HLA-A2.

[0155] In some embodiments, the ABR-1 may comprise a heavy chain comprising the VH-1, and the ABR-2 may comprise a heavy chain comprising the VH-2.

[0156] In some embodiments, the ABR-1 may comprise a heavy chain comprising the VH-1, and the ABR-2 may comprise or consist of an α-chain comprising a / the Vα of a TCR and / or a β-chain comprising a / the Vβ of the TCR.

[0157] In certain embodiments, the ABR-1 may consist of said heavy chain or may further comprise a light chain comprising a VL-1.

[0158] In certain embodiments, the heavy chain may comprise a heavy chain constant region, optionally comprising one or more heavy chain constant domains and / or a hinge. In some cases, the one or more heavy chain constant domains and / or the hinge may: comprise one or more of CH3, CH2, and CH1, further optionally comprising CH2 and CH3 or comprising CH1, CH2, and CH3; and / or may individually be of an IgG, IgA, IgE, IgD, or IgM class, optionally an IgG1, IgG2, IgG3, or IgG4 subclass. 50 Attorney Docket No.: 1160430.004613

[0159] In certain embodiments, the ABR-1 may comprise or consist of a half antibody variant of a heavy chain-only antibody (HCAb). In certain embodiments, the ABR-1 may comprise or consist of a half antibody variant of an immunoglobulin (Ig) molecule, optionally of an IgG, IgE, or IgD.

[0160] In certain embodiments, the ABR-1 may comprise a structure described in FIG.1D. In particular embodiments, the ABR-1 may comprise the top left (boxed) structure or the bottom left structure thereof.

[0161] In certain embodiments, the ABR-2 may consist of said heavy chain comprising the VH-2 or may further comprise a light chain comprising the VL-2.

[0162] In certain embodiments, the ABR-2 may consist of an α-chain comprising a / the Vα of a TCR and / or a β-chain comprising a / the Vβ of the TCR.

[0163] In certain embodiments, the heavy chain may comprise a heavy chain constant region, optionally comprising one or more heavy chain constant domains and / or a hinge. In some cases, the one or more heavy chain constant domains and / or the hinge may comprise one or more of CH3, CH2, and CH1, further optionally comprising CH2 and CH3 or comprising CH1, CH2, and CH3; and / or (b-2) may individually be of an IgG, IgA, IgE, IgD, or IgM class, optionally an IgG1, IgG2, IgG3, or IgG4 subclass.

[0164] In embodiments, the α-chain may further comprise a α-chain constant domain (Cα) and / or the β-chain may further comprise a β-chain constant domain (Cβ). In particular embodiments, the α-chain may comprise the Vα and the Cα in the direction from the N- terminus to the C-terminus and / or the β-chain may comprise the Vβ and the Cβ in the direction from the N-terminus to the C-terminus.

[0165] In certain embodiments, the ABR-2 may comprise or consist of a half antibody variant of a heavy chain-only antibody (HCAb). In certain embodiments, the ABR-2 may comprise or consist of a half antibody variant of an immunoglobulin (Ig) molecule, optionally of an IgG, IgE, or IgD.

[0166] In certain embodiments, the ABR-2 may comprise a structure described in FIG.1D. In particular embodiments, the ABR-2 may comprise the bottom center structure, the top left (boxed) structure, the top center structure, or the bottom left structure thereof.

[0167] In particular embodiments, the ABR-1 may comprise the top left (boxed) structure of FIG.1D and the ABR-2 may comprise the bottom center structure of FIG.1D. 51 Attorney Docket No.: 1160430.004613

[0168] In particular embodiments, the ABR-1 may comprise the top right structure of FIG. 1D and the ABR-2 comprises an α-chain comprises a / the Vα and a / the Cα optionally in the direction from the N-terminus to the C-terminus and a β-chain comprises a / the Vβ and a / the Cβ optionally in the direction from the N-terminus to the C-terminus.

[0169] In certain embodiments, the ABR-1 and the ABR-2 may be associated with or linked to each other via one or more disulfide bonds or a linker, optionally a peptide linker, further optionally a flexible peptide linker. In certain embodiments, the multi-specific antibody may comprise the ABR-1 and the ABR-2 at 1:1, optionally one each.

[0170] In certain embodiments, the multi-specific antibody may comprise a structure depicted in any one of FIG.2A, optionally the top left (boxed) structure, the bottom left structure, or the top right structure thereof. For example, the ABR-A and ABR-B of FIG.2A may be or may correspond to the ABR-1 and the ABR-2, respectively. For example, the VH- A and VH-B of FIG.2A may be or may correspond to the VH-1 and the VH-2, respectively. For example, the VL-A (if present) of FIG.2A may be or may correspond to the VL-1 (if present). For example, the VL-B (if present) of FIG.2A may be or may correspond to the VL-2 (if present).

[0171] In certain embodiments, the multi-specific antibody may comprise a structure depicted in any one of FIG.2C, optionally the bottom left (solid box) structure or a variant thereof on the bottom, the top left structure (dashed box), or the top center or right structure thereof, optionally wherein: (i) ABR-A and ABR-B of FIG.2C are the ABR-1 and the ABR- 2, respectively; (ii) VH-A of FIG.2C is the VH-1; (iii) Vα-B of FIG.2C is the Vα of ARB- 2; and / or (iv) Vβ-B of FIG.2C is the Vβ of ARB-2.

[0172] In some embodiments, the ABR-1 may comprise a sdAb comprising the VH-1 and / or a nanobody comprising the VH-1, and the ABR-2 may comprise a heavy chain comprising the VH-2 and optionally a light chain comprising the VL-2. In some embodiments, the ABR- 1 may comprise a sdAb comprising the VH-1 and / or a nanobody comprising the VH-1, and the ABR-2 may comprise an α-chain comprising a Vα and a β-chain comprising a Vβ.

[0173] In certain embodiments, the ABR-2 may comprise a heavy chain comprising the VH- 2 and a light chain comprising the VL-2. In particular embodiments the ABR-2 may consist of said heavy and light chains.

[0174] In particular embodiments the ABR-2 may comprise or consist of an Ig molecule comprising two said heavy chains and two said light chains, or a multimer of said Ig 52 Attorney Docket No.: 1160430.004613 molecule. In particular embodiments the ABR-2 may comprise or consist of an IgG, IgA, IgE, IgD, or IgM, optionally an IgG1, IgG2, IgG3, or IgG4. In particular embodiments the ABR-2 may comprise or consist of a Fab comprising the VH-2 and the VL-2. In particular embodiments the ABR-2 may comprise or consist of a scFv comprising the VH-2 and the VL-2, optionally wherein the scFv comprises the VH-2, a linker, and the VL-2 in the direction from the N-terminus to the C-terminus or the VL-2, a linker, and the VH-2 in the direction from the N-terminus to the C-terminus. In particular embodiments the ABR-2 may comprise or consist of a sdAb comprising the VH-2. In particular embodiments, the ABR-1 may comprise a sdAb comprising the VH-1 and the ABR-2 may comprise or consist of an Ig molecule.

[0175] In particular embodiments the ABR-2 may comprise or consist of a pair of an α-chain comprising a / the Vα and an Cα and a β-chain comprising a / the Vβ and a Cβ. In some cases, the α-chain comprises the Vα and the Cα in the direction from the N-terminus to the C- terminus and / or said β-chain comprises the Vβ and the Cβ in the direction from the N- terminus to the C-terminus.

[0176] In certain embodiments, the ABR-1 and the ABR-2 may be associated with or linked to each other via a linker, optionally a peptide linker, further optionally a flexible peptide linker, or via one or more disulfide bonds.

[0177] In certain embodiments, the multi-specific antibody may comprise the ABR-1 and the ABR-2 at 1:1, 2:1, 4:1, 6:1, or 8:1, optionally comprising one, two, three, four, five, six, seven, or eight ABR-1 and one or two ABR-2.

[0178] In certain embodiments, the multi-specific antibody comprises a structure depicted in any one of FIG.2B, optionally the top left structure thereof. For example, the ABR-A and the ABR-B of FIG.2B may be or may correspond to the ABR-1 and the ABR-2, respectively. For example, the VH-A and the VH-B of FIG.2B may be or may correspond to the VH-1 and the VH-2, respectively, or the VH-1 and the Vα, respectively. For example, the VL-A (if present) of FIG.2B may be or may correspond to the VL-1 (if present). For example, the VL-B (if present) of FIG.2B may be or may correspond to the VL-2 (if present) or the Vβ (if present).

[0179] In some embodiments, the ABR-1 may comprise: at least one Ig constant domain and / or hinge, optionally one or more of a heavy chain constant domain 1 (CH1), a hinge, a 53 Attorney Docket No.: 1160430.004613 heavy chain constant domain 2 (CH2), a heavy chain constant domain 3 (CH3), a light chain constant domain (CL); a fragment crystallizable (Fc) region, and / or a TCR constant domain.

[0180] In certain embodiments, the CH1, hinge, CH2, and / or the CH3 may individually be of an IgG, IgA, IgE, IgD, or IgM class, optionally of an IgG1, IgG2, IgG3, and / or IgG4 subclass. In certain embodiments, the CL is of a kappa isotype (CLκ) or a lambda isotype (CLλ). In certain embodiments, the Fc region may be of an IgG, IgA, IgE, IgD, or IgM class, optionally of an IgG1, IgG2, IgG3, and / or IgG4 subclass. In certain embodiments, the TCR constant domain may be a Cα or a Cβ.

[0181] In some embodiments, the ABR-2 may comprise: at least one Ig constant domain and / or hinge, optionally one or more of a CH1, a hinge, a CH2, a CH3, a CL, a Fc region, and / or a TCR constant domain.

[0182] In certain embodiments, the CH1, hinge, CH2, and / or the CH3 may individually be of an IgG, IgA, IgE, IgD, or IgM class, optionally of an IgG1, IgG2, IgG3, and / or IgG4 subclass. In certain embodiments, the CL may be a CLκ or a CLλ. In certain embodiments, the Fc region may be of an IgG, IgA, IgE, IgD, or IgM class, optionally of an IgG1, IgG2, IgG3, and / or IgG4 subclass. In certain embodiments, the TCR constant domain may be a Cα or a Cβ.

[0183] In certain embodiments, the multi-specific antibody may comprise common light chains. For example, the VL-1 (if present) and the VL-2 (if present) may have the same or essentially the same amino acid sequences.

[0184] In certain embodiments, the multi-specific antibody may comprise a heavy chain constant region (CH), optionally a CH1, which is engineered to promote pairing with a CLκ over a CLλ, optionally wherein the CH1 engineering comprises the incorporation of one of the variant CH1 domains described in WO2021067404.

[0185] In certain embodiments, the multi-specific antibody may comprise a CH, optionally a CH1, which is engineered to promote pairing with a CLλ over a CLκ, optionally wherein the CH1 engineering comprises the incorporation of one of the variant CH1 domains and / or variant CL domains described in WO2021067404.

[0186] In certain embodiments, the multi-specific antibody may comprise a CH, optionally a CH1, which is engineered to promote pairing with an engineered CL comprised in the multi- specific antibody over another CL, optionally wherein the combination of the CH engineering 54 Attorney Docket No.: 1160430.004613 and the CL engineering comprises the incorporation of one of the variant CH1 domains and / or variant CL domains described in WO2022150787.

[0187] In certain embodiments, the multi-specific antibody may comprise at least two CHs having different amino acid sequences, optionally at least two CH3s having different amino acid sequences, which are engineered to promote heteromeric paring between the two CHs over homomeric pairing, optionally wherein the CH3 engineering comprises the incorporation of one of the variant CH3 domains described in WO2022150785.

[0188] In some embodiments, the multi-specific antibody may bind monovalently, bivalently, trivalently, or tetravalently to: (a) CD28, optionally human CD28; (b) a cancer antigen, optionally a TSA or a TAA, optionally CD20; (c) CD3, optionally human CD3; (d) any one of the antigens selected from those listed in Table 2; and / or (e) any one of the cancer antigens, optionally any one of the TSAs or any one of the TAAs, selected from those listed in Table 2.

[0189] Another aspect of the present disclosure provides nucleic acids (e.g., one or more nucleic acids) and vectors (e.g., one or more vectors, such as a vector or a combination of two or more vectors) and / or constructs that includes any of the nucleic acids according to the present disclosure.

[0190] In some embodiments, a nucleic acid (e.g., one or more isolated or recombinant nucleic acids, such as a nucleic acid or a combination of two or more nucleic acids) is provided and may encode any of the anti-human CD3 antibodies or antigen-binding antibody fragments described above or herein or any of the multi-specific antibodies disclosed above or herein.

[0191] In certain embodiments, the nucleic acid may comprise a VH-1-encoding nucleic acid, which may optionally have at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to any one of the VH-encoding sequences of Table 13D, 1D, or 24D. In certain embodiments, the nucleic acid may comprise a VL-1-encoding nucleic acid, which may optionally have at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity to any one of the VL-encoding sequences of Table 13D, 1D, or 24D. 55 Attorney Docket No.: 1160430.004613

[0192] In some embodiments, a vector (e.g., one or more vectors, such as a vector or a combination of two or more vectors) is provided and may comprise any of the nucleic acids encoding any of the anti-human CD3 antibodies or antigen-binding antibody fragments described above or herein or any of the multi-specific antibodies disclosed above or herein.

[0193] In certain embodiments, the vector may be an expression vector.

[0194] In certain embodiments, the vector may comprise a plasmid, a viral vector (optionally adenoviral, lentiviral, or retroviral), a lipid-based vector, a self-replicating RNA vector, a virus-like particle, a polymer-based vector, and / or a nanoparticle, optionally a lipid-based nanoparticle.

[0195] Another aspect of the present disclosure provides isolated and / or recombinant host cells and a population of such cells.

[0196] In some embodiments, the cell may comprise, be transfected with, be transformed with, or be transduced with any of the nucleic acids and / or vectors and / or constructs.

[0197] In certain embodiments, the cell may be non-mammalian, optionally bacterial, yeast, fungal, protozoa, plant, or insect, bacterial. In certain embodiments, the cell may be mammalian, optionally human, non-human primate, monkey, rabbit, rodent, hamster, rat, or mouse.

[0198] Another aspect of the present disclosure provides compositions such as pharmaceutical compositions.

[0199] In some embodiments, the composition may comprise: (A) at least one of: any of the anti-human CD3 antibodies or antigen-binding antibody fragments disclosed above or herein or any of the multi-specific antibodies disclosed above or herein; any of the nucleic acids disclosed above or herein; any of the vectors disclosed above or herein; and any of the isolated and / or recombinant host cells disclosed above or herein; and (B) a pharmaceutically acceptable carrier / excipient.

[0200] In certain embodiments, the composition may further comprise an additional agent, optionally an adjuvant or a therapeutic agent.

[0201] Another aspect of the present disclosure provides in vivo methods such as methods of treating a disease, disorder, or condition in a subject or methods of treating a subject in need thereof of treating a subject comprising a disease, disorder, or condition. 56 Attorney Docket No.: 1160430.004613

[0202] In some embodiments, the method may comprise administering to the subject an effective amount of at least one of: any of the anti-human CD3 antibodies or antigen-binding antibody fragments disclosed above or herein or any of the multi-specific antibodies disclosed above or herein; any of the nucleic acids disclosed above or herein; any of the vectors disclosed above or herein; any of the isolated and / or recombinant host cells disclosed above or herein; and / or any of the compositions disclosed above or herein.

[0203] In certain embodiments, the subject may be a mammal, optionally a human, a non- human primate, a monkey, a horse, a cow, sheep, a goat, a pig, a dog, a cat, a rabbit, a rodent, a hamster, a rat, or a mouse. In certain embodiments, the subject may be a non-mammalian vertebrate, optionally a bird, fish, an amphibian, or a reptile.

[0204] In certain embodiments, the method may further comprise administering to the subject an additional agent, optionally an adjuvant or a therapeutic agent.

[0205] In some embodiments, the disease, disorder, or a condition may comprise cancer or a neoplastic condition, an autoimmune disease, a neurodegenerative disease, an infectious disease, an inflammatory disease, or another disease.

[0206] In certain embodiments, the cancer may be a solid cancer, optionally chosen from: one or more of mesothelioma, malignant pleural mesothelioma, non-small cell lung cancer, small cell lung cancer, squamous cell lung cancer, large cell lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, esophageal adenocarcinoma, breast cancer, glioblastoma, ovarian cancer, colorectal cancer, prostate cancer, cervical cancer, skin cancer, melanoma, renal cancer, liver cancer, brain cancer, thymoma, sarcoma, carcinoma, uterine cancer, kidney cancer, gastrointestinal cancer, urothelial cancer, pharynx cancer, head and neck cancer, rectal cancer, esophagus cancer, or bladder cancer, or a metastasis thereof.

[0207] In certain embodiments, the cancer may be a liquid cancer, optionally chosen from: chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), multiple myeloma, acute lymphoid leukemia (ALL), Hodgkin lymphoma, B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), small lymphocytic leukemia (SLL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma (DLBCL), DLBCL associated with chronic inflammation, chronic myeloid leukemia, myeloproliferative neoplasms, follicular lymphoma, pediatric follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma (extranodal marginal zone 57 Attorney Docket No.: 1160430.004613 lymphoma of mucosa-associated lymphoid tissue), Marginal zone lymphoma, myelodysplasia, myelodysplastic syndrome, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, splenic lymphoma / leukemia, splenic diffuse red pulp small B-cell lymphoma, hairy cell leukemia-variant, lymphoplasmacytic lymphoma, a heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, primary cutaneous follicle center lymphoma, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+large B-cell lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, primary effusion lymphoma, B-cell lymphoma, acute myeloid leukemia (AML), or unclassifiable lymphoma.

[0208] In certain embodiments, the autoimmune or inflammatory disease may be psoriasis, rheumatoid arthritis, autoimmune arthritis, type I diabetes, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, scleroderma, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, pemphigus vulgaris, Sjogren’s syndrome, Addison’s disease, Behcet’s disease, Schmidt syndrome, celiac disease, dermatomyositis, autoimmune vitiligo, Graves’ disease, Hashimoto thyroiditis, Kawasaki disease, pernicious anemia, autoimmune vasculitis, or fibrosis.

[0209] In certain embodiments, the cancer may be a neurodegenerative disease may be Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Friedreich ataxia, Lewy body disease, spinal muscular atrophy, motor neuron disease, multiple sclerosis, Batten disease, Creutzfeldt-Jakob disease.

[0210] In certain embodiments, the infectious disease may be a viral, bacterial, fungal, yeast, protozoan, prion or parasitic disease, optionally wherein (1) the viral disease is human immunodeficiency virus (HIV), hepatitis virus (optionally hepatitis A, B, or C virus), human papillomavirus (HPV), herpes simplex virus (HSV) (optionally HSV-1 or HSV-2), enterovirus, human cytomegalovirus, adenovirus, rhinovirus, Pox virus, Influenza virus, coronavirus (optionally MERS-CoV, SARS-CoV, or SARS-CoV-2, or common human coronavirus), norovirus, West Nile Virus, Zika virus, poliovirus, Ebola virus, or dengue virus (DENV) infection, (2) the bacterial disease is Salmonella, Escherichia coli, Mycobacterium tuberculosis, methicillin-resistant staphylococcus aureus (MRSA), Clostridium difficile, 58 Attorney Docket No.: 1160430.004613 Streptococcus pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Helicobacter pylori, Neisseria gonorrhoeae, Vibrio vulnificus, and / or (3) the fungal disease is Aspergillosis, Candida, Candida auris, Cryptococcus neoformans, Pneumocystis jirovecii, Mucormycetes, Taloromyces, ringworm, Blastomyces, Coccidioides, Cryptococcus gattii, Histoplasma, Paracoccidioides, or Sporothrix infection.

[0211] One aspect of the present disclosure provides methods of activating and / or depleting a CD3+ cell. The method may comprise contacting any of the anti-human CD3 antibodies or antigen-binding antibody fragments of disclosed above or herein or any of the multi-specific antibodies disclosed above or herein with a CD3+ cell. A further aspect of the present disclosure provides methods of preventing, suppressing, or reversing CD3+ cell activation. The method may comprise contacting any of the non-stimulatory anti-human CD3 antibodies or antigen-binding antibody fragments of disclosed above or herein or any of the multi- specific antibodies disclosed above or herein containing any of the non-stimulatory anti- human CD3 antibodies or antigen-binding antibody fragments with a CD3+ cell.

[0212] In some embodiments, the CD3+ cell may be a T cell or a cell of T cell lineage.

[0213] In certain embodiments, the CD3+ cell may be a T cell progenitor cell, a CD4+ T cell, a helper T cell, a regulatory T cell, a CD8+ T cell, a naïve T cell, an effector T cell, a memory T cell, a stem cell memory T (TSCM) cell, a central memory T (TCM) cell, an effector memory T (TEM) cell, a terminally differentiated effector memory T cell, a tumor-infiltrating lymphocyte (TIL), an immature T cell, a mature T cell, a cytotoxic T cell, a mucosa- associated invariant T (MAIT) cell, a TH1 cell, a TH2 cell, a TH3 cell, a TH17 cell, a TH9 cell, a TH22 cell, a follicular helper T cells, and a / b T cell, a g / d T cell, a Natural Killer T (NKT) cell, a cytokine-induced killer (CIK) cell, a lymphokine-activated killer (LAK) cell, a perforin-deficient cell, a granzyme-deficient cell, a B cell, a myeloid cell, a monocyte, a macrophage, or a dendritic cell.

[0214] In certain embodiments, the CD3+ cell may be a cancer cell of T cell lineage, optionally leukemia or lymphoma, further optionally non-Hodgkin lymphoma, or optionally T-lymphoblastic lymphoma (T-LBL) / T-lymphoblastic leukemia (T-ALL), peripheral T-cell lymphoma, T-cell prolymphocytic leukemia (T-PLL). In some cases, the T-lymphoblastic lymphoma / leukemia may be acute lymphoblastic leukemia (ALL) and / or precursor T- lymphoblastic lymphoma. In some cases, the peripheral T-cell lymphoma may be one or more of cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome, etc), adult 59 Attorney Docket No.: 1160430.004613 T-cell leukemia / lymphoma, angioimmunoblastic T-cell lymphoma (AITL), extranodal natural killer / T-cell lymphoma, nasal type (ENKTL / NKTCL), enteropathy-associated intestinal T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T cell lymphoma (MEITL), anaplastic large cell lymphoma (ALCL) (e.g., primary cutaneous ALCL, systemic ALCL, breast implant-associated ALCL, etc), or peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS).

[0215] In some embodiments, the contacting may occur in vitro, ex vivo, in vivo or a combination thereof.

[0216] One aspect of the present disclosure provides methods of directing a CD3+ cell to a target cell. The method may comprise comprising contacting any of the multi-specific antibodies with a CD3+ cell and a target cell expressing the second antigen.

[0217] In some embodiments, the CD3+ cell may be a T cell or a cell of T cell lineage. In certain embodiments, the CD3+ cell may be a T cell progenitor cell, a CD4+ T cell, a helper T cell, a regulatory T cell, a CD8+ T cell, a naïve T cell, an effector T cell, a memory T cell, a stem cell memory T (TSCM) cell, a central memory T (TCM) cell, an effector memory T (TEM) cell, a terminally differentiated effector memory T cell, a tumor-infiltrating lymphocyte (TIL), an immature T cell, a mature T cell, a cytotoxic T cell, a mucosa- associated invariant T (MAIT) cell, a TH1 cell, a TH2 cell, a TH3 cell, a TH17 cell, a TH9 cell, a TH22 cell, a follicular helper T cells, and a / b T cell, a g / d T cell, a Natural Killer T (NKT) cell, a cytokine-induced killer (CIK) cell, a lymphokine-activated killer (LAK) cell, a perforin-deficient cell, a granzyme-deficient cell, a B cell, a myeloid cell, a monocyte, a macrophage, or a dendritic cell.

[0218] In some embodiments, the target cell may be a cell associated with or involved in the pathogenesis or pathology of a disease, a disorder, or a condition optionally any of the disease, disorder, or condition disclosed above or herein.

[0219] In some embodiments, the method is a method of eliciting cytotoxicity to a cell expressing a target molecule of interest. In some embodiments, the second antigen may be any of the second antigens disclosed above or herein. In some embodiments, the contacting may occur in vitro, ex vivo, or in vivo. In some embodiments, the method may be a method for eliciting cytotoxicity to the target cell. 60 Attorney Docket No.: 1160430.004613

[0220] Another aspect of the present disclosure provides methods of manufacturing any of the anti-CD3 antibodies or antigen-binding fragments or any of the multi-specific antibodies according to any of the embodiments described herein.

[0221] In some embodiments, the method may comprise (a) culturing cells comprising one or more nucleic acid encoding an anti-CD3 antibody or antigen-binding antibody fragment or any multi-specific antibody disclosed above or herein in a condition that allows for expression of the antibody or antigen-binding antibody fragment or the multi-specific antibody, and (b) harvesting and purifying the antibody or antigen-binding antibody fragment or the multi-specific antibody from the cell culture from (a).

[0222] In certain embodiments, the introducing occurs in vitro, ex vivo, or in vivo.

[0223] Another aspect of the present disclosure provides methods of manufacturing an isolated and / or recombinant host cell according to any of the embodiments described herein or the population of such cells.

[0224] In some embodiments, the method may comprise introducing one or more nucleic acids encoding an anti-CD3 antibody or antigen-binding antibody fragment and / or one or more vectors comprising such one or more nucleic acids into one or more cells.

[0225] In certain embodiments, the introducing occurs in vitro, ex vivo, or in vivo or a combination thereof.

[0226] In some embodiments, the method may comprise: introducing a nucleic acid according to any of the embodiments described herein and / or a vector according to any of the embodiments described herein into one or more cells. In certain embodiments, the introducing may occur in vitro, ex vivo, or in vivo or a combination thereof.

[0227] Any of the anti-CD3 antibodies and antigen-binding fragments according to the present disclosure, any of the multi-specific antibodies according to the present disclosure, any of the nucleic acids according to the present disclosure, any of the vectors according to the present disclosure, any of the isolated and / or recombinant host cells according to the present disclosure or a population of such cells, and / or any of the pharmaceutical compositions according to the present disclosure may be for use in medicine, use in treating a disease, disorder, or condition, and / or use in the preparation of a medicament for use in medicine 61 Attorney Docket No.: 1160430.004613

[0228] In some embodiments, the disease, disorder, or condition may comprise any one or more of those disclosed above or herein.

[0229] The present disclosure further encompasses use of any of the anti-CD3 antibodies and antigen-binding fragments according to the present disclosure, any of the multi-specific antibodies according to the present disclosure, any of the nucleic acids according to the present disclosure, any of the vectors according to the present disclosure, any of the isolated and / or recombinant host cells according to the present disclosure or a population of such cells, and / or any of the pharmaceutical compositions according to the present disclosure for the manufacture of a medicament for treatment of a disease, disorder, or condition, and / or for use in any of the methods (e.g., methods of treating, methods of activating. methods of targeting, methods of manufacturing, etc) disclosed above or herein.

[0230] In some embodiments, the disease, disorder, or condition may comprise any one or more of those disclosed above or herein.

[0231] The foregoing and other objects, features, and advantages of particular embodiments of the disclosure will be apparent from the following description and illustrations in the accompanying figures. BRIEF DESCRIPTION OF THE FIGURES

[0232] FIGS.1-2 provide exemplary and non-limiting embodiments of various antibody, antigen-binding antibody fragment, and multi-specific antibody structures which may comprise any of the anti-CD3 antibody sequences disclosed herein. In some cases, antibody, antigen-binding antibody fragment, and multi-specific antibody structures disclosed herein may also comprise one or more domains of a non-antibody immune receptor such as a T cell receptor (TCR). In FIGS.1-2, the following rules apply unless otherwise indicated: (1) Each domain is presented as a rectangle with a text therein showing the domain name (e.g., CH3, VH, etc); (2) a set of multiple domains connected with each other represents a polypeptide (e.g., a heavy chain polypeptide, a light chain polypeptide, etc); (3) the direction of domains within a polypeptide is according to the direction of the text showing domain names, from the N-terminus to the C-terminus; (4) a linker or a hinge may be used between domains as necessary and a disulfide bond(s) may exist between polypeptides (and / or within a domain or within a polypeptide), perhaps to allow correct formation of the antigen-binding site(s), even when the FIGS do not explicitly show a linker, a hinge, or a disulfide bond; (5) any of the constant domains (e.g., CH1, CH2, and / or CH3 domain(s), or Cα and / or Cβ domain(s)) 62 Attorney Docket No.: 1160430.004613 shown in FIGS may be omitted or replaced with another constant domain when possible and / or desired and, when appropriate, may be replaced with a hinge or a linker; (6) constant domains shown as rectangles with no pattern (i.e., open) may individually comprise a corresponding wild-type sequence or may comprise one or more amino acid substitutions relative to a wild-type sequence; (7) hinge and CH1, CH2, and CH3 domains may individually be of any (heavy chain) isotype; (8) when more than one hinges are present in a structure, the hinges may or may not be of the same isotype, when more than one CH1 domains are present in a structure, the CH1 domains may or may not be of the same isotype, when more than one CH2 domains are present in a structure, the CH2 domains may or may not be of the same isotype, and when more than one CH3 domains are present in a structure, the CH3 domains may or may not be of the same isotype; (9) light chain constant (CL) domain may be a kappa CL domain or a lambda CL domain; (10) when more than one CL domains are present in a structure, all CL domains may be kappa CLs or all CL domains may be lambda CLs, or alternatively at least one CL may be a kappa CL and at least one CL may be a lambda CL domain; (11) when both kappa and lambda CL domains are present, the CH1 domains paired to the CL domains may, in some instances, be variant CH1 domains, one of which may be a variant CH1 that preferentially binds to a kappa CL and another CH1 domain may be a variant CH1 that preferentially binds to a lambda CL (e.g., having kappa and lambda CLs and kappa-preferring CH1 and lambda-preferring CH1 in a molecule potentially allows for efficient manufacturing); (12) VH and VL domains paired with each other Vα and Vβ domains paired with each other in FIGS form an antigen-binding site for an epitope; (13) in a given VH-VL pair, the VL may be omitted even if VL is shown in FIGS, if the VH alone gives sufficient specificity to a cognate antigen (e.g., nanobody), and similarly in a given Vα- Vβ pair, the Vα or the Vβ may be omitted even if both Vα and Vβ are shown in FIGS, if the Vβ alone or the Vα alone, respectively, gives sufficient specificity to a cognate antigen (e.g., nanobody); (14) a VH domain not shown to be paired with a VL domain in FIGS may form an antigen-binding site for an epitope without a VL domain (e.g., HCAb, nanobody, etc); (15) when there are more than one antigen-binding sites, the antigen-binding sites may all bind to the same epitope or at least one or more antigen-binding sites may bind to a different epitope; and (16) a tag (e.g., for purification) or a linker (e.g., for conjugation) may be attached to any appropriate site (including but not limited to an N-terminus or a C-terminus of a polypeptide) of the depicted antibody structure. 63 Attorney Docket No.: 1160430.004613

[0233] FIGS.1A-1D provide some exemplary and non-limiting embodiments of structures which may be comprised by or contained in (i) various anti-CD3 antibodies and antigen- binding antibody fragments and / or (ii) various antigen-binding regions (ABRs) which may be contained in multi-specific antibodies according to the present disclosure.

[0234] FIG.1A provides some basic, exemplary antibody structures. The antibody on the top left (boxed) is an exemplary, standard heavy chain-only antibody (HCAb) (also referred to as heavy chain antibody), in which hinges or disulfide bods are not explicitly shown. The boxed antibody may, for example, comprise a hinge between VH and CH2 and one or more disulfide bond(s) (dotted line(s)) may be present between the hinges as shown in top right. As shown in the bottom left, one or two CH1 domains may be further added to the boxed antibody (although two CH1 domains are shown, one may optionally be omitted). Such an antibody may, for example, comprise a hinge between CH1 and CH2 and one or more disulfide bond(s) (dotted line(s)) may be present between the hinges as shown in bottom right. One or more of the CH2 and / or CH3 domains, although shown, may optionally be omitted as appropriately. Hinges and disulfide bonds, such as but not limited to those shown in the right antibody structures, may be present even if not explicitly shown, in any of the structures shown in FIGS and described herein.

[0235] FIG.1B provides some variants of the antibody structures provided in FIG.1A and the description thereof. As shown in the top left, some variant antibody structures may further comprise a VL to be paired with the VH of the boxed antibody of FIG.1A to form an antigen-binding site. Such an antibody may, for example, comprise: a hinge between VH and CH2 and one or more disulfide bond(s) (dotted line(s)) between the hinges (top center and top right); and one or more disulfide bond(s) (dotted line(s)) between VH and VL (top center) or between hinge and VL (top right). As shown in the bottom left, some variant antibody structures may comprise a VL-CL to be paired with the VH-CH1 of the bottom left antibody of FIG.1A to form an antigen-binding site. Such an antibody may, for example, comprise: a hinge between CH1 and CH2 and one or more disulfide bond(s) (dotted line(s)) between the hinges (top center and top right); and one or more disulfide bond(s) (dotted line(s)) between CH1 and CL (top center) or between hinge and CL (top right). One or more of the CH2 and / or CH3 domains, although shown, may optionally be omitted as appropriately. In further variant antibodies, the VH and VL positions in one or more of the VH-VL pairs may optionally be swapped, and / or the CH1 and CL positions in one or more of the CH1-CL pairs may optionally be swapped. 64 Attorney Docket No.: 1160430.004613

[0236] FIG.1C provides additional variants of the antibody structures in which both CH2 and CH3 domains are omitted from the structures provided in FIGS.1A-1B and the description thereof. In the top, the second from the top, the third from the top, and the bottom of the left structures, the CH2 and CH3 domains are omitted from the top left of FIG.1A, the bottom left of FIG.1A, the top left of FIG.1B, the bottom left of FIG.1B, respectively, and the two VH domains, the two VH-CH1, the two VH-VL pair, and the two Fab (or Fab-like) fragments are linked in any appropriate manner, e.g., directly or indirectly, for example via a polypeptide linker or another linker, or chemically. For example, any of such structures may comprise a hinge on the C-terminal end / side of VH (the top and third from the top in the center and right) or on the C-terminal end / side of CH1 (second from the top and the bottom in the center and right) and one or more disulfide bond(s) (dotted line(s)) between the hinges (center and right); and one or more disulfide bond(s) (dotted line(s)) between VH and VL (third from the top in the center), between CH1 and CL (the bottom in the center), between hinge and VL (third from the top on the right), or between hinge and CL (bottom right). As described above, the VH and VL positions in one or more of the VH-VL pairs may optionally be swapped, and / or the CH1 and CL positions in one or more of the CH1-CL pairs may optionally be swapped.

[0237] FIG.1D provides additional variations of the antibody structures. The present disclosure encompasses the “half antibody” variants of any of the antibody structures disclosed herein such as those provided in FIGS.1A-1C and the description thereof. Non- limiting, exemplary “half antibody” structures are depicted in FIG.1D. The top left structure (boxed) is a “half antibody” variant of the boxed antibody structure provided in FIG.1A. “Half antibody” variants of the bottom left of FIG.1A, the top left of FIG.1B, and the bottom left of FIG.1A are shown in the bottom left, top center, and bottom center, respectively. “Half antibody” variants of the top, second from the top, third from the top, and the bottom in the left of FIG.1A are shown in the top, second from the top, third from the top, and the bottom, respectively, on the right. In these structures on the right, even though CH2 and / or CH3 may not be present, a hinge or a portion thereof may optionally be present, although not explicitly shown, for example on the C-terminal end / side of the VH (top or third from the top) or of the CH1 (second from the top or the bottom). As also described above, one or more disulfide bond(s) (dotted line(s)) between CH1 and CL (top center) or between hinge and CL (top right), although not explicitly shown, may optionally be present for 65 Attorney Docket No.: 1160430.004613 example to properly form an antigen-binding site. The structure in the third from the top on the right may encompass an scFv (e.g., VH-linker-VL or VL-linker-VH).

[0238] FIGS.2A-2C provide schematics and some exemplary and non-limiting embodiments of structures which may be comprised by or contained in antibodies comprising more than one antigen-binding regions (ABRs) such as multi-specific antibodies according to the present disclosure. In addition to the above-noted rules (1)-(16), the following rules applies unless otherwise indicated: (17) VH-A and VL-A (or Vα-A and Vβ-A) form an antigen-binding site specific for antigen A or epitope A, VH-B and VL-B (or Vα-B and Vβ- B) form an antigen-binding site for antigen B or epitope B, and so on; (18) VL-A, even when shown, may optionally be omitted if VH-A is capable of binding to antigen A or epitope A without VL-A, VL-B, even when shown, may optionally be omitted if VH-B is capable of binding to antigen A or epitope A without VL-A, and so on; (18) all of antigens A, B, etc or epitopes A, B, etc may be different from each other, or not all of antigens A, B, etc or epitopes A, B, etc may be different from each other; (19) stripe and dotted constant domains paired with each other (e.g., a set of CH1 and CL domains, a set of two CH3 domains, or a set of Cα and Cβ domains) in FIGS may or may not be a set of constant domains one or both of which domains is / are engineered to promote preferential pairing between the constant domains of the set (e.g., over pairing with another constant domain). One or more additional antigen-binding regions (e.g., one which binds to antigen C or epitope C (ABR-C), one which binds to antigen D or epitope D (ABR-D), and so on) may be further added to any of these structures to provide further multi-specific antibody structures.

[0239] FIG.2A provides a general schematic (left) of antigen-binding structures which bind to antigens A and B and / or epitopes A and B (“AB-A / B”), which may be contained in antibodies, antigen-binding antibody fragments, and multi-specific antibodies (e.g., bispecific antibodies) of the present disclosure, and some exemplary structures according to the general schematic (center and right). The general schematic (left) shows that an AB-A / B may for example comprise (1) at least an antigen-binding region which bind to antigen A and / or epitope A (ABR-A) paired with (2) at least an antigen-binding region which bind to antigen B and / or epitope B (ABR-B). Antigens A and B may be same or different from each other, and epitopes A and B may be same or different from each other. The ABR-A may comprise any structures which allows for binding to antigen A and / or epitope A, such as but not limited to those described herein or depicted in any of FIGS.1A-1D, and the ABR-B may comprise any structures which allows for binding to antigen B and / or epitope B, such as but not limited 66 Attorney Docket No.: 1160430.004613 to those described herein or depicted in any of FIGS.1A-1D. The ABR-A and the ABR-B may be paired via any appropriate mechanism, such as but not limited to one or more disulfide bonds. In the top center structure (boxed), the ABR-A may comprise the boxed structure of FIG.1D, and the ABR-B may comprise the bottom center structure of FIG.1D. In the top right structure, the ABR-A may comprise the boxed structure of FIG.1D, and the ABR-B may comprise the boxed structure of FIG.1D. In the bottom center structure, the ABR-A may comprise the bottom left structure of FIG.1D, and the ABR-B may comprise the bottom center structure of FIG.1D. In the bottom right structure, the ABR-A may comprise the bottom left structure of FIG.1D, and the ABR-B may comprise the bottom left structure of FIG.1D.

[0240] FIG.2B provides another general schematic (left) of “AB-A / B”, which may be contained in antibodies, antigen-binding antibody fragments, and multi-specific antibodies (e.g., bispecific antibodies) of the present disclosure, and some exemplary structures according to the general schematic (center and right). The general schematic (left) shows that an AB-A / B may for example comprise (1) one or more (six are depicted but any appropriate numbers may be used) antigen-binding regions which bind to antigen A and / or epitope A (ABR-A) linked to (2) at least an antigen-binding region which bind to antigen B and / or epitope B (ABR-B). Antigens A and B may be same or different from each other, and epitopes A and B may be same or different from each other. The ABR-A may comprise any structures which allows for binding to antigen A and / or epitope A, such as but not limited to those described herein or depicted in any of FIGS.1A-1D, and the ABR-B may comprise any structures which allows for binding to antigen B and / or epitope B, such as but not limited to those described herein or depicted in any of FIGS.1A-1D. The ABR-A and the ABR-B may be linked directly or indirectly, via any appropriate mechanism, such as but not limited to one or more polypeptide linkers or other linkers, or chemically. An ABR-A may be linked to the N-terminus or the C-terminus of a polypeptide of an ABR-B, and an ABR-B may be linked to the N-terminus or the C-terminus of a polypeptide of an ABR-A. In the top center structure (boxed), the ABR-A may comprise the top right structure of FIG.1D, and the ABR-B may comprise the bottom left structure of FIG.1B. Although six VH-A domains are shown, any of these VH-A domains may be omitted and / or additional one or more VH-A domains may be further added. In the top right structure, the ABR-A may comprise the top right structure of FIG.1D, and the ABR-B may comprise the bottom right structure of FIG. 1D. Although four VH-A domains are shown, any of these VH-A domains may be omitted 67 Attorney Docket No.: 1160430.004613 and / or additional one or more VH-A domains may be further added. In the bottom left structure, the ABR-A may comprise the top right structure of FIG.1D, and the ABR-B may comprise the third from the top on the right of FIG.1D, wherein the structure comprises an scFv of the VH-linker-VL format. Although two VH-A domains are shown, any of these VH- A domains may be omitted and / or additional one or more VH-A domains may be further added. In the bottom right structure, the ABR-A may comprise the top right structure of FIG. 1D, and the ABR-B may comprise the third from the top on the right of FIG.1D, wherein the structure comprises an scFv of the VL-linker-VB format. Although two VH-A domains are shown, any of these VH-A domains may be omitted and / or additional one or more VH-A domains may be further added.

[0241] FIG.2C provides some variants of the antibody structures provided in FIGS.2A-2B and the description thereof. Variants of any of the antibody structures provided in FIGS.2A- 2B and the description thereof may comprise a set of Vα and Vβ (of a TCR) instead of a set of VH and VL and / or comprise a set of Cα and Cβ (of a TCR) instead of a set of CH1 and CL. For example, the top left (dashed box) provides some variants of the boxed structure of FIG.2A, which variants comprise a set of Vα and Vβ instead of a set of VH and VL and comprise a set of Cα and Cβ instead of a set of CH1 and CL contained the boxed antibody of FIG.2A. The top center and right provide some variant structures comprising a single-chain Vα-Vβ (the C-terminus of Vα is directly or indirectly conjugated to the N-terminus of Vβ) or a single-chain Vβ-Vα (the C-terminus of Vβ is directly or indirectly conjugated to the N- terminus of Vα), to which one or more VHH is attached indirectly (e.g., via a linker such as but not limited to a G4S, G3S, or GS linker) or directly. Although two VHHs are depicted, any other numbers (e.g., 1, 3, 4, etc) of VHH(s) may be present. The VHH(s) may be attached to any part of the single-chain Vα-Vβ or Vβ-Vα. For example, a VHH may be attached to the N-terminus and / or the C-terminus of Vα and / or Vβ. The bottom left (solid box) provides particular variant antibody structures comprising a pair of (Vα-Cα) and (Vβ- Cβ), to which a VHH is attached indirectly (e.g., via a linker such as but not limited to a G4S, G3S, or GS linker) or directly. Although one VHH is depicted, any other numbers (e.g., 2, 3, 4, etc) of VHHs may be present. The VHH(s) may be attached to any part of (Vα-Cα) and / or (Vβ-Cβ). For example, a VHH may be attached to the N-terminus of Vα and / or Vβ and / or the C-terminus of Cα and / or Cβ (bottom structures). In some cases, VHHs may be present in tandem (e.g., two VHHs in tandem may be attached to a pair of (Vα-Cα) and (Vβ-Cβ)). In 68 Attorney Docket No.: 1160430.004613 any of the variant structures described above or herein, the Vα and Vβ positions in one or more of the Vα-Vβ pairs may optionally be swapped, and / or the Cα and Cβ positions in one or more of the Cα-Cβ pairs (if present) may optionally be swapped. In some cases, one or more of the Cα and Cβ pairs may optionally be omitted. DETAILED DESCRIPTION

[0242] The present disclosure generally relates to anti-CD3 antibodies and antigen-binding fragments. The CD3-binding domains may be used in monospecific antibodies or antibody fragments or incorporated in multi-specific antibodies. Anti-CD3 antibodies and antigen-binding antibody fragments

[0243] “Cluster of Differentiation 3” or “CD3”, generally refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans and non-human primates) and rodents (e.g., mice and rats), unless otherwise indicated, including, for example, CD3ε, CD3δ, and CD3γ chains. The term encompasses “full-length,” unprocessed CD3 (e.g., unprocessed or unmodified CD3ε, CD3δ, or CD3γ), as well as any form of CD3 that results from processing in the cell. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. Human CD3 includes, for example: human CD3ε (such as SEQ ID NO: 61 (NP_000724.1), which is 207 amino acids in length comprising a signal sequence at residues 1-21, an ectodomain at residues 22-126, a transmembrane domain at residues 127-152, and an intracellular domain at residues 153-207); human CD3δ (such as SEQ ID NO: 62 (NCBI Reference Sequence: XP_054226455.1), which is 171 amino acids in length comprising a signal sequence at residues 1-21, an ectodomain at residues 22-105, a transmembrane domain at residues 106- 126, and an intracellular domain at residues 127-171); and human CD3γ protein (such as SEQ ID NO: 63 (NCBI Reference Sequence: NP_000064.1), which is 182 amino acids in length comprising a signal sequence at residues 1-22, an ectodomain at residues 23-116, a transmembrane domain at residues 117-137, and an intracellular domain at residues 138-182. Cynomolgus CD3 includes, for example: cynomolgus CD3ε (such as SEQ ID NO: 71 (NCBI Reference Sequence: XP_015290838.2), which is 198 amino acids in length comprising a signal sequence at residues 1-21, an ectodomain at residues 22-117, a transmembrane domain at residues 118-138, and an intracellular domain at residues 139-198); cynomolgus CD3δ (such as SEQ ID NO: 72 (NCBI Reference Sequence: XP_014971304.1), which is 171 amino 69 Attorney Docket No.: 1160430.004613 acids in length comprising a signal sequence at residues 1-21, an ectodomain at residues 22- 105, a transmembrane domain at residues 106-126, and an intracellular domain at residues 127-171); and cynomolgus CD3γ protein (such as SEQ ID NO: 73 (NCBI Reference Sequence: NP_001270839.1), which is 181 amino acids in length comprising a signal sequence at residues 1-22, an ectodomain at residues 23-113, a transmembrane domain atresidues 114-134, and an intracellular domain at residues 135-181. “CD3 N27” (or“CD3eN27”) and “CD3 N13” (or “CD3eN13”) refer to the N-terminal 27 amino acids (e.g.,SEQ ID NO: 75) and the N-terminal 13 amino acids (e.g., SEQ ID NO: 76), respectively, of CD3, and optionally containing chemical modifications or conjugations made thereto, such as addition of an Fc. Mouse CD3 includes, for example: mouse CD3ε (such as SEQ ID NO: 81 (GenBank: ADD13994.1), which is 189 amino acids in length comprising a signal sequence at residues 1-20, an ectodomain at residues 21-108, a transmembrane domain at residues 109- 134, and an intracellular domain at residues 135-189); mouse CD3δ (such as SEQ ID NO: 82 (GenBank: ADK78994.1), which is 173 amino acids in length comprising a signal sequence at residues 1-21, an ectodomain at residues 22-105, a transmembrane domain at residues 106- 126, and an intracellular domain at residues 127-173); and mouse CD3γ protein (such as SEQ ID NO: 83 (GenBank: ADD13993.1), which is 182 amino acids in length comprising a signal sequence at residues 1-22, an ectodomain at residues 23-116, a transmembrane domain at residues 117-137, and an intracellular domain at residues 138-182.

[0244] As used herein, the terms "polypeptide," "peptide," and "protein" refer to polymers of amino acids of any length. The terms also encompass an amino acid polymer that has been modified; for example, to include disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component.

[0245] The term “antibody” is used herein in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multi-specific antibodies (e.g., bispecific antibodies (BsAb)), single domain antibodies, heavy chain-only antibodies, whole antibodies, and antibody fragments [preferably those fragments that exhibit the desired antigen-binding activity (i.e., antigen- binding fragments)].

[0246] An “isolated antibody” is one which has been separated from a component of its natural environment. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse 70 Attorney Docket No.: 1160430.004613 phase HPLC). For review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0247] A “monoclonal antibody” or “mAb” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variant antibodies (e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation), such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.

[0248] The term “epitope” refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. The term “epitope” also refers to a site on an antigen to which B and / or T cells respond. It also refers to a region of an antigen that is bound by an antibody. Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of the structural epitopes and have those residues that directly contribute to the affinity of the interaction. Epitopes may also be conformational, that is, composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and / or specific charge characteristics.

[0249] The term “format” as used herein in relation to antibodies and antigen-binding antibody fragments refers to the structure of an antibody or antigen-binding antibody fragment having all the domains contained in a referenced antibody structure, wherein the domains are placed in essentially the same orientation as in the referenced antibody structure. For example, by “an IgG format” it is meant that all the domains contained in a native IgG antibody are present in the same orientation as in a native IgG antibody. That is, an antibody of an IgG format comprises two sets of a heavy chain (comprising a VH, a CH1, a hinge, a CH2, and a CH3 from the N-terminus to the C-terminus) and a light chain (comprising a VL and a CL from the N-terminus to the C-terminus), wherein one heavy chain and one light chain are paired with each other and the other heavy chain and the other light chain are paired 71 Attorney Docket No.: 1160430.004613 with each other, further wherein the two heavy chains are associated with each other. Each domain or part of an antibody of an IgG format may have the same sequence as the corresponding domain or part of a wild-type or reference IgG or may contain modifications (e.g., amino acid sequence changes, glycosylation, etc.) relative to the corresponding domain or part of a wild-type or reference IgG.

[0250] The terms “intact antibody” and “whole antibody” or the like are used herein interchangeably and refer to an antibody having a structure (variable and constant domain construction) substantially similar to a native antibody. In some instances, an antibody comprises a heavy (H) chain (e.g., a structure same as or substantially similar to the structure of a single domain antibody (sdAb), a nanobody, a heavy chain-only antibody (HCAb), a camelid antibody, a shark antibody, and IgNAR, etc). In some instances, an antibody comprises heavy (H) and light (L) chains interconnected by disulfide bonds (e.g., a structure same as or substantially similar to the structure of human Ig). There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. For example, an intact IgG (or IgD or IgE) antibody comprises two immunoglobulin heavy chains and two immunoglobulin light chains. Therefore, in some instances, an antibody according to the present disclosure may comprise two pairs of heavy and light chains interconnected by disulfide bonds, or an antigen-binding fragment(s) thereof. Some intact antibody comprises multiple units each comprising two pairs of heavy and light chains interconnected by disulfide bonds. For example, an intact IgA comprises two units and an intact IgM comprises five units. Therefore, in other instances, an antibody according to the present disclosure may instead comprise multiple (e.g., two, three, four, five, and so on) units each comprising two pairs of heavy and light chains interconnected by disulfide bonds, or an antigen-binding fragment(s) thereof.

[0251] Each heavy chain is comprised of: a heavy chain variable domain (VH); and a heavy chain constant region (CH), which is typically comprised of domains CH1, CH2 and CH3. Each light chain, when present, is comprised of: a light chain variable domain (VL); and a light chain constant domain (CL). The VH and VL can be further subdivided into regions of hypervariability formed by polypeptide loops, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each VH or VL polypeptide is composed of three CDRs and four FRs, arranged from amino- 72 Attorney Docket No.: 1160430.004613 terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. CDRs in a heavy chain are designated “CDRH1,” “CDRH2,” and “CDRH3,” respectively. FRs in a heavy chain are designated “FRH1,” “FRH2,” “FRH3,” and “FRH4,” respectively. CDRs in a light chain are designated “CDRL1,” “CDRL2,” and “CDRL3,” respectively. FRs in a light chain are designated “FRL1,” “FRL2,” “FRL3,” and “CDRL3,” respectively. An array of V genes encoding antigen-binding heavy chain variable domain (VH) and light chain variable domain (VL) are generated through combinatorial rearrangement of genetic segments. The rearrangement produces a diverse repertoire of antibodies with capacity to recognize a wide range of antigens.

[0252] In some embodiments, antibodies of the present disclosure include antibodies with antigen-binding domains having only a variable heavy domain of a heavy chain, referred to herein as a “VHH.” Such antibodies may include heavy chain-only antibodies, referred to herein as “HCAbs.” Such antibodies include two paired heavy chains with each having a VHH connected to CH2-CH3 constant regions via a hinge region (no CH1 region and no light chains). HCAbs may be synthetic or naturally derived. For example, HCAbs are naturally expressed by the species camelid, which includes but is not limited to camels, dromedaries, and llamas. In addition to conventional VH / VL antibodies, camelids produce HCAbs which include the smallest known naturally-occurring VHH binding domain (Hamers-Casterman et al., Nature.1993). HCAbs have several structural differences relative to conventional antibodies such as human IgGs. For example, HCAbs provide antigen specificity without being paired with a VL domain, while conventional antibodies have a VH domain and a VL domain, which typically as a pair provide antigen specificity. HCAbs lack CH1 domains, and many camelid HCAbs include shorter hinge regions (e.g., SEQ ID NOS: 91, 93, 95, and 98). Because of these differences, HCAbs have a smaller molecular weight of about 90 kDa compared to conventional antibodies (such as human IgGs), which are about 150 kD (Spinelli et al., Nat Structural Biol.1996). A further distinguishing feature of VHHs lies within a region of FR2 that would otherwise contact a light chain. Several amino acids that are highly conserved in conventional VH domains are substituted with hydrophilic residues in VHHs, which functionally impart solubility (Harmsen et al., Appl Microbiol Biotechnol.2007).

[0253] Like their conventional counterparts (e.g., human IgGs), camelid HCAbs may achieve high affinity via a similar mechanism of hypermutation in the variable region and selection of cells expressing high-affinity antibodies. It is the relatively small size of HCAbs and their 73 Attorney Docket No.: 1160430.004613 VHH binding domains that piques interest as it is recognized to offer potential developability and therapeutic benefits. Compared to conventional antibodies, HCAbs often exhibit higher solubility and higher thermostability (Bannas et al., Front Immunol.2017; Ikeuchi et al., Sci Rep.2021). The relatively small size and lack of light chains also typically facilitates simplified protein production. Camelid single chain antibodies have been observed to interact with antigens deemed inaccessible to conventional antibodies, thus use of HCAbs and corresponding VHH binding domains may expand the universe of druggable targets. The phenomenon is in some cases guided by relatively long heavy chain CDR3 (CDRH3) domains. The relatively long CDRH3 often loops away from the antibody scaffold, forming what has been characterized in some instances as a fingerlike extension that can access cavities characteristic of enzyme active sites. In the structure of VHH cAb-Lys3 for example, the 24 amino acid CDRH3 grants the antibody access to the active site of lysozyme, blocking enzyme activity (DeGenst et al., PNAS.2006).

[0254] VHH discovery may be carried out by immunizing camelids such as llamas against an antigen of interest and screening outputs for HCAbs (or structural variants thereof) based on, e.g., affinity to the antigen (see, e.g., Trempe et al., Methods Mol Biol.2022; Nunes-Silva et al., Sci Rep.2014; Arras et al., mAbs.2023, the contents of each of which are herein incorporated by reference in their entirety).

[0255] Therefore, in certain embodiments, antibodies of the present disclosure include antibodies with VHH anti-CD3 antigen-binding domains (i.e., the VH is sufficient in providing specificity to CD3). Such antibodies may include anti-CD3 HCAbs. Such antibodies include two paired heavy chains with each having a VHH connected to CH2-CH3 constant regions via a hinge region (no CH1 region and no light chains). Such antibodies may further encompass “half HCAbs,” also referred to herein as “VHH-Fc” antibodies. Such antibodies include one heavy chain containing a VHH connected to CH2-CH3 via a hinge region (no CH1 and no light chain). The hinge region may include the hinge region of human IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0256] In certain embodiments of the disclosure, the FRs of the antibody (or antigen-binding fragment) may be identical to or substantially identical to the human germline-encoded sequences (e.g., heavy chain FR sequences encoded by the VH1-02, VH1-03, VH1-18, VH1- 69, VH2-05, VH3-07, VH3-09, VH3-11, VH3-21, VH3-23, VH3-30, VH3-33, VH3-48, VH3-49, VH3-66, VH3-72, VH4-0B, VH4-31, VH4-34, VH4-39, VH4-4A, VH4-4B, VH4- 59, VH5-51, VH1-46 germline; and / or light chain FR sequences encoded by the VK4-01, 74 Attorney Docket No.: 1160430.004613 VK1-12, VK3-11, VK1-39, VK1-33, VK-2-28, VK3-15, VK1-05, VK3-20, VL2-11, VL1- 51, VL1-40, VL2-11, VL6-57, VL2-14, or VL1-44 germline) or may be naturally or artificially modified relative to these germline-encoded sequences, for example to sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0257] The phrase “heavy chain” or “HC” is used in its broadest sense and encompasses a polypeptide comprising at least one immunoglobulin heavy chain domain or part (i.e., at least one of VH, CH1, hinge, CH2, and / or CH3). Similarly, the phrase “light chain” or “LC” is used in its broadest sense and encompasses a polypeptide comprising at least one immunoglobulin light chain domain (i.e., at least one of VL and / or CL).

[0258] The numbering of amino acid residues in antibody variable and / or constant domains may be based on any appropriate numbering schemes, methods, and definitions, e.g., based on numbering schemes such as EU numbering (as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)), IMGT numbering, Kabat numbering, Chothia numbering, Martin numbering, Gelfand numbering, or Honneger’s numbering); and / or structurally (see e.g., NCBI online tool, IgBlast; Dondelinger et al., Front Immunol.2018 Oct 16;9:2278; http: / / www.bioinf.org.uk / abs / info.html#cdrid; http: / / opig.stats.ox.ac.uk / webapps / newsabdab / sabpred / anarci / ), crystallography, e.g., by using x-ray crystallography to visualize specific epitope contact residues; or a combination thereof). The EU numbering system is used for constant domains in the present specification unless otherwise specified.

[0259] According to IMGT (the international ImMunoGeneTics information system for immunoglobulins or antibodies, T cell receptors, MH, immunoglobulin superfamily IgSF and MhSF), the CH1 domain, the hinge region, the CH2 domain, and the CH3 domain correspond to the amino acid positions 118-215, 216-230, 231-340, and 341-446, respectively (EU numbering). The terms “CH1 domain”, “hinge”, “CH2 domain”, and “CH3” are used in a broad sense herein to encompass any naturally occurring, corresponding heavy chain constant domain and / or region allotypes and variants thereof, which may comprise fewer or more amino acids (e.g., a CH1 domain may comprise a portion of a hinge region) and / or amino acid modification(s). 75 Attorney Docket No.: 1160430.004613

[0260] Various standard sequences (corresponding to different allotypes) of the constant domains of human IgG1, IgG2, IgG3, and IgG4 are known in the field and may be found for example in Vidarsson et al., Front Immunol. 2014 Oct 20;5:520 and US Patent No.9150663, the disclosures of which are hereby incorporated by reference herein in their entirety herein. Again these reference sequences are intended to be exemplary as Applicant intends for human IgG1, IgG2, IgG3, and IgG4 sequences to include any naturally occurring human IgG1, IgG2, IgG3, and IgG4 allotype.

[0261] An exemplary CH1 domain of a human IgG1 may comprise the amino acid sequence of SEQ ID NO: 1 or 2. An exemplary hinge of a human IgG1 may comprise the amino acid sequence of SEQ ID NO: 11; an exemplary hinge of a human IgG2 may comprise the amino acid sequence of SEQ ID NO: 12; an exemplary hinge of a human IgG3 may comprise the amino acid sequence of SEQ ID NO: 13; and an exemplary hinge of a human IgG4 may comprise the amino acid sequence of SEQ ID NO: 14. An exemplary CH2 domain of a human IgG1 may comprise the amino acid sequences of SEQ ID NOS: 21. An exemplary CH3 domain of a human IgG1 may comprise the amino acid sequence of SEQ ID NO: 31, 32, 33, or 34, an exemplary CH3 domain of a human IgG2 may comprise the amino acid sequence of SEQ ID NO: 35, an exemplary CH3 domain of a human IgG3 may comprise the amino acid sequence of SEQ ID NO: 36, and an exemplary CH3 domain of a human IgG4 may comprise the amino acid sequence of SEQ ID NO: 37, and a C-terminal K (lysine) may be added to any of such CH3 sequences. Any variants of such exemplary sequences may be used in conjunction with anti-CD3 variable sequences described herein.

[0262] In case of camelids, a hinge may be a long hinge or a short hinge, e.g., depending on the class or subclass of the antibody. An exemplary long hinge of an alpaca HCAb may comprise the amino acid sequence of SEQ ID NO: 90; and an exemplary short hinge of an alpaca HCAb may comprise the amino acid sequence of SEQ ID NO: 91. An exemplary camel IgG1a may have a long hinge comprising the amino acid sequence of SEQ ID NO: 92; and an exemplary camel IgG1b may have a short hinge comprising the amino acid sequence of SEQ ID NO: 93. An exemplary llama IgG1a may have a long hinge comprising the amino acid sequence of SEQ ID NO: 94; and an exemplary llama IgG1b may have a short hinge comprising the amino acid sequence of SEQ ID NO: 95. An exemplary llama IgG2b may have a long hinge comprising the amino acid sequence of SEQ ID NO: 96 or 97. An exemplary llama IgG2c may have a short hinge comprising the amino acid sequence of SEQ ID NO: 98. Alternative llama IgG2 long hinge sequence may comprise SEQ ID NO: 99. In 76 Attorney Docket No.: 1160430.004613 some embodiments, the hinge of an antibody according to the present disclosure may comprise any of these camelid hinge sequences or a variant or a truncated version thereof. In certain embodiments, the hinge of an antibody according to the present disclosure may comprise SEQ ID NO: 91, 93, 95, or 98 or a variant thereof.

[0263] “Fc region” is a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region, including native sequence Fc regions and variant Fc regions. A human IgG heavy chain Fc region can extend from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991.

[0264] The phrase “effector function” of an antibody refers to biological activities attributable to the Fc region of an antibody, which varies by antibody class or isotype. Exemplary effector functions include: complement (e.g., C1q) binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0265] There are two major light chain isotypes, kappa (κ) and lambda (λ), and the corresponding light chain constant domains are called kappa CL domain (CLκ domain) and lambda CL domain (CLλ domain), respectively.

[0266] According to IMGT, the CLκ domain is the amino acid positions 108-214 (EU numbering). An exemplary CLκ domain of a human IgG may comprise the amino acid sequence of SEQ ID NO: 41. According to IMGT, the CLλ domain is the amino acid positions 107-215 (EU numbering). An exemplary CL λ domain of a human IgG may comprise the amino acid sequence of SEQ ID NO: 42.

[0267] The terms “CLκ domain” “CLλ domain” are used in a broad sense herein to encompass any naturally occurring, corresponding light chain constant domain and / or region allotypes and variants thereof, which may comprise fewer or more amino acids and / or amino acid modification(s). 77 Attorney Docket No.: 1160430.004613

[0268] An “antigen-binding fragment” or “antigen-binding antibody fragment” refers to a portion of an intact antibody or to a combination of portions derived from one or more intact antibody that binds the antigen to which the intact antibody binds (in this case, CD3). An antigen-binding fragment of an antibody includes any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that comprises an antigen-binding antibody domain (e.g., a VH domain, or VH and VL domains) that specifically binds an antigen to form a complex. Exemplary antigen-binding fragments include, but are not limited to, Fv; fragment antigen-binding (“Fab”) fragment; single-chain Fab (scFab); Fab' fragment; Fab' containing a free sulfhydryl group (‘Fab'-SH’); F(ab')2 fragment; F(ab')3fragment; diabody; triabody; tetrabody; linear antibodies; single-chain antibody molecules (e.g., single-chain variable fragment (scFv), half antibody, nanobody or VH only, or VL only); and multi-specific antibodies formed from one or more antibody fragments such as the foregoing. In some embodiments, the antigen-binding fragments of the anti-CD3 antibodies described herein are scFvs. In some embodiments, antigen-binding fragments of anti-CD3 antibodies described herein are VHHs. In some cases, an “antigen- binding fragment” or “antigen-binding antibody fragment” may further comprise to a portion or one or more domains of an immune receptor such as but not limited to a T cell receptor (TCR), e.g., one or more variable domains thereof (e.g., Vα and / or Vβ) and one or more constant domains thereof (e.g., Cα and / or Cβ).

[0269] A “half antibody” variant of a given antibody or antigen-binding antibody fragment as used herein refers to an antigen-binding antibody structure which comprises a symmetrical half or an essentially symmetrical half of the given antibody or antigen-binding antibody fragment. Therefore, when the given antibody or antigen-binding fragment is a homodimer (or an essentially homodimer), the half antibody variant thereof comprises the corresponding monomer. Therefore, the term “half molecule” or “half antibody” when referring to IgG, IgE, or IgD, which may also be referred to as “half IgG”, “half IgE”, or “half IgD”, respectively, refers to a set of one heavy chain (comprising a VH, a CH1, a hinge, a CH2, and a CH3) and one light chain (comprising a VL and a CL) of the referenced antibody. Similarly, the term “half molecule” or “half antibody” when referring to an HCAb or a camelid antibody (or camel IgG, such as camel IgG2 or camel IgG3), may also be referred to as “half HCAb,” “VHH-Fc,” or “half camelid.” Such half antibodies include one heavy chain comprising a VH (a VHH), a hinge, a CH2 and a CH3 of a referenced HCAb or camelid antibody. Further similarly, a half antibody variant of an IgNAR comprises one polypeptide comprising a VH, 78 Attorney Docket No.: 1160430.004613 a hinge (or a linker), a CH1, a CH2, a CH3, a CH4, and a CH5. Since a half antibody variant of a camel antibody and a half antibody variant of an IgNAR are both single-chain molecules, they may also be referred to as a single-chain variant of a camel antibody and a single-chain variant of an IgNAR, respectively.

[0270] For a review of certain antibody fragments, see, e.g., Hudson et al. Nat. Med.9:129- 134 (2003). For discussion of Fab and F(ab′)2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Pat. No.5,869,046. Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993 / 01161; Hudson et al. Nat. Med.9:129- 134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med.9:129-134 (2003). Single- domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain (e.g., a VHH) or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, e.g., U.S. Pat. No.6,248,516 B1). Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein.

[0271] The term "scFv," “single-chain Fv,” or “single-chain variable fragment” refers to a fusion protein comprising at least one VH and at least one VL of an antibody, wherein the VH and the VL are contiguously linked and wherein the scFv retains the specificity of the antibody from which it is derived (the antibody from which the VH and the VL are derived). Unless specified, as used herein an scFv may have the VH and the VL in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide. For example, the VH and the VL may be linked via a linker, such as a synthetic and / or flexible polypeptide linker, and the scFv may be capable of being expressed as a single chain polypeptide. When a linker connects the VH and the VL, a scFv may comprise the structure of VL-linker-VH or VH- linker-VL, in a direction from the N-terminus to the C-terminus. When a linker connects the VH and the VL, the linker may be any appropriate linker such as but not limited to any of the linkers described herein. In some cases, the VH and the VL are additionally or alternatively connected by one or more disulfide bonds. In certain cases, the VH and / or the VL sequences may be modified (e.g., one or more amino acids may be substituted) to comprise a cysteine residue to allow for such a disulfide bond (e.g., see Weatherill et al., Protein Eng Des Sel. 79 Attorney Docket No.: 1160430.004613 2012 Jul;25(7):321-9.). For a review of scFv fragments, see, e.g., Pluckthün, in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., (Springer- Verlag, New York), pp.269-315 (1994); see also WO 93 / 16185; and U.S. Pat. Nos. 5,571,894 and 5,587,458.

[0272] The term “linker” as used herein refers to a construct of variable length connecting two or more domains or portions of a polypeptide or connecting two or more polypeptides. In some cases, a linker is used to confer flexibility, improved spatial organization, proximity, etc and in such a case may be referred to as a flexible linker. Exemplary linkers may comprise one or more amino acids, optionally between 1-50 amino acids, such as one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty amino acids. In some embodiments, the linker may predominantly or entirely consist of G, S, and / or A amino acid residues. In some embodiments, the linker may comprise an amino acid sequence which comprises or consists of the amino acid sequence selected from the group consisting of GGGGS (SEQ ID NO: 51, which may also be called “G4S”), GGGS (SEQ ID NO: 52, which may also be called “G3S”), GGGGGS (SEQ ID NO: 53, which may also be called “G5S”), G, GG, GGG, GS, SG, GGS (which may also be called “G2S”), GSG, SGG, GSS, SGS, and SSG. In some embodiments, the linker may comprise an amino acid sequence which comprises or consists of multiple repeats (e.g., two, three, four, five, or more repeats) of the amino acid sequence selected from the group consisting of G, GS, SG, GGS, GSG, SGG, GSS, SGS, SSG, and any combinations thereof. When the linker comprises or consists of multiple repeats of G5S (SEQ ID NO: 53), G4S (SEQ ID NO: 51), G3S (SEQ ID NO: 52), G2S, GS, or G, the linker may optionally called a (G5S)n linker (SEQ ID NO: 11820), a (G4S)n linker (SEQ ID NO: 11821), a (G3S)n linker (SEQ ID NO: 11822), a (G2S)n linker (SEQ ID NO: 11823), a (GS)n linker (SEQ ID NO: 11824), or a (G)n linker (SEQ ID NO: 11825), respectively (n is a natural number, optionally selected from 1-20, e.g., 2, 3, 4, 5, etc). In particular embodiments, the linker may comprise two or three repeats of SEQ ID NO: 51, i.e., have the sequence of GGGGSGGGGS (SEQ ID NO: 54) or GGGGSGGGGSGGGGS (SEQ ID NO: 55), respectively, and may optionally be called a (G4S)2linker (SEQ ID NO: 54) or a (G4S)3linker (SEQ ID NO: 55), respectively. In some embodiments, the linker may be a TVAAP linker (SEQ ID NO: 56), ASTKGP linker (SEQ ID NO: 57), or GSEPKSS linker (SEQ ID NO: 58). 80 Attorney Docket No.: 1160430.004613

[0273] An “antigen-binding region” refers to a portion of an antibody or antigen-binding fragment with specificity for an antigen.

[0274] An “anti-CD3 antibody” refers to an antibody or an antigen-binding fragment capable of binding to CD3, e.g., CD3ε, CD3δ, and / or CD3γ, e.g., human CD3ε, CD3δ, CD3γ with sufficient affinity and / or specificity such that the antibody is useful for an intended purpose, e.g., as a diagnostic and / or therapeutic agent or as a laboratory agent in targeting CD3.

[0275] In some embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species, e.g., human and cynomolgus cross-reactive, human and murine cross-reactive, and / or human, cynomolgus, and murine cross-reactive.

[0276] The term “specifically binds,” or “binds specifically to”, or the like, means that an antibody or antigen-binding antibody fragment forms a complex with an antigen that is relatively stable under physiologic conditions. Specific binding can be characterized by an equilibrium dissociation constant of at least about 1 x10-6M or less (e.g., a smaller KD denotes a tighter binding). Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. As described herein, antibodies have been identified by surface plasmon resonance (SPR), e.g., CARTERRA®. Moreover, multi-specific antibodies that bind to CD3 and one or more additional antigens or epitopes, or a bispecific, trispecific, or tetraspecific antibody that respectively binds to two, three, or four different regions of CD3 and / or different regions of an additional antigen are nonetheless considered antibodies that “specifically bind”, as used herein. In certain embodiments, the antibodies disclosed herein display equilibrium dissociation constants (and hence specificities) of about 1 x 10-6M; about 1 x 10-7M; about 1 x 10-8M; about 1 x 10-9M; about 1 x 10-10M; between about 1 x 10-6M and about 1 x 10-7M; between about 1 x 10-7M and about 1 x 10-8M; between about 1 x 10-8M and about 1 x 10-9M; or between about 1 x 10-9M and about 1 x 10-10M. Affinity

[0277] Affinity may be measured using any appropriate methods, such as by surface plasmon resonance (SPR), e.g., CARTERRA® or BIACORE™, biolayer interferometry (BLI) measurements using, e.g., a FORTEBIO Octet® HTX instrument (Pall Life Sciences), or solution-affinity ELISA.

[0278] In some embodiments, the anti-CD3 antibody or an antigen-binding fragment thereof according to the present disclosure or a CD3-binding domain contained in a 81 Attorney Docket No.: 1160430.004613 monospecific or multi-specific antibody according to the present disclosure may have high affinity to CD3. In many situations antibodies with high affinity provides various benefits including but not limited to the need of a lower antibody dose or amount to achieve an intended effect (e.g., as a reagent used in in vitro experiments to achieve an intended level of binding, as a therapeutic to achieve an intended therapeutic effect) and / or a reduced risk of causing side effects (e.g., as an agent to be administered to a subject, such as a therapeutic, to cause e.g., reduced inflammation).

[0279] In certain embodiments, such a “high affinity” antibody may have a KD of about 10-9M or smaller or in some cases in the order of 10-9M, e.g., about 1x10-9M to <5x10-9M. In certain embodiments, such a “high affinity” antibody may have a KD of about 10-10M or smaller or in some cases in the order of 10-10M, e.g., about 1x10-10M to <10x10-10M.

[0280] For example, Antibody Nos.2, 6, and 23 bind to human CDε / δ with KD values in this affinity range (about 1x10-9M to <5x10-9M by SPR using CARTERRA®). For example, Antibody Nos.4, 14, 15, 19, and 21 bind to human CDε / δ with KD values in this affinity range (about 1x10-9M to <5x10-9M by BLI using OCTET®). Among the humanized antibodies described herein tested for affinity, for example, Antibody Nos.21-h1, 21-h3, 21- h7, 21-h9, 21-h12, 21-h13, 21-h14, 21-h15, 21-h24, 21-h43, 21-h44, 4-h1, 4-h2, 4-h3, 4-h4, 4-h5, 4-h6, 4-h7, 4-h8, 4-h9, 4-h10, 4-h11, 4-h12, 4-h13, 4-h14, 4-h16, 4-h17, 4-h18, 4-h19, 4-h20, 4-h22, 4-h26, 4-h28, 4-h29, 14-h1, 14-h4, 14-h6, 14-h7, 14-h10, 14-h11, 14-h19, 14- h21, 14-h24, 14-h27, 14-h46, 15-h1, 15-h2, 15-h3, 15-h4, 15-h5, 15-h6, 15-h7, 15-h8, 15-h9, 15-h10, 15-h11, 15-h12, 15-h13, 15-h15, 15-h16, 15-h22, 19-h28, 19-h29, 25-h1, 25-h2, 25- h4, 25-h5, 25-h8, and 25-h12 bind to human CDε / δ with KD values in this affinity range (about 1x10-9M to <5x10-9M by BLI using OCTET®). Such binding KD values may be determined using any appropriate antibody format via any appropriate methods, such as but not limited to surface plasmon resonance (SPR), e.g., CARTERRA®, BIACOR, biolayer interferometry (BLI) measurements using, e.g., a FORTEBIO Octet® HTX instrument (Pall Life Sciences), or solution-affinity ELISA. In some cases, a buffer, solvent, or reagent having a neutral or physiological pH may be used for measuring KD values.

[0281] In some embodiments, the anti-CD3 antibody or an antigen-binding fragment thereof according to the present disclosure or a CD3-binding domain contained in a monospecific or multi-specific antibody according to the present disclosure may not have high affinity to CD3 or may have low affinity to CD3. In some situations, without wishing to be bound by theory, antibodies which do not have high affinity (e.g., “medium affinity”) or which have “low affinity” may be beneficial. For example, in some cases, such relatively low 82 Attorney Docket No.: 1160430.004613 affinity (i.e., medium or low affinity) binding to CD3 may avoid overstimulation of CD3- expressing cells, and in some cases it may help prevent T cell exhaustion and / or overt inflammation (e.g., when used as a therapeutic or during preparation of a therapeutic, such as T cell-based therapeutic).

[0282] In certain embodiments, such an antibody having “medium affinity” to CD3 may have a KD in the range of 5 x10-9M to <10 x10-9M.

[0283] For example, Antibody Nos.3, 4, 5, 7, 8, 14, 15, 19, 20, 21, 22, 24, 26, and 28 bind to human CDε / δ with KD values in this affinity range, and Antibody No.23 bind to cynomolgus CDε / δ with KD values in this affinity range (about 5x10-9M to <10x10-9M by SPR using CARTERRA®). Among the humanized antibodies described herein tested for affinity, for example, Antibody Nos.21-h8, 19-h2, 19-h3, and 19-h6 bind to human CDε / δ with KD values in this affinity range (about 5x10-9M to <10x10-9M by BLI using OCTET®).

[0284] In certain embodiments, an antibody having “low affinity” to CD3 may have a KD of 10-8M or larger or in some cases in the range of 1x10-8M to <5x10-8M or in the range of 1x10-8M to <10x10-8M (or higher).

[0285] For example, Antibody Nos.9, 10, 11, 12, 13, 16, and 17 bind to human CDε / δ with KD values in this affinity range, Antibody Nos.1 and 24 bind to cynomolgus CDε / δ with KD values in this affinity range, and Antibody No.24 binds to mouse CDε / δ with KD values in this affinity range (about 1x10-8M to <10x10-8M (or higher) by SPR using CARTERRA®). Among the humanized antibodies described herein tested for affinity, for example, Antibody Nos.14-h2 binds to human CDε / δ with KD values in this affinity range 1x10-8M to <10x10-8M (or higher) by BLI using OCTET®).

[0286] Such binding KD values may be determined using any appropriate antibody format via any appropriate methods, such as but not limited to surface plasmon resonance, e.g., BIACOR, biolayer interferometry measurements using, e.g., a FORTEBIO Octet® HTX instrument (Pall Life Sciences), or solution-affinity ELISA. In some cases, a buffer, solvent, or reagent having a neutral or physiological pH may be used for measuring KD values.

[0287] By the term “slow off rate”, is meant an antibody that dissociates from the cognate antigen (e.g., CD), with a rate constant (Koff ) of 1 x 10-31 / s or less, preferably 1 x 10-41 / s or less, as determined by surface plasmon resonance, e.g., BIACORE™ or a FORTEBIO Octet® HTX instrument (Pall Life Sciences). 83 Attorney Docket No.: 1160430.004613

[0288] In some embodiments, the monovalent KDis measured for an antibody having a HCAb format, a half HCAb format, an IgG format, a half IgG format, a structure shown in any of FIGS.2A-2C, or the top center structure (boxed) or bottom center structure in FIG. 2A or the bottom left (solid box) or its variants in the bottom shown in FIG.2C.

[0289] Antibodies produced through a process known as affinity maturation, during which point mutations are introduced and selected by the immune system based on improved binding characteristics (Alberts et al. Molecular Biology of the Cell.4thedition, 2002). Therefore, in some embodiments, the antibodies disclosed herein may encompass those obtained by affinity maturation and may also encompass subjecting antibodies disclosed herein to affinity maturation. Non-stimulatory anti-CD3 antibodies

[0290] In some embodiments, anti-CD3 antibodies of the present disclosure are non- stimulatory anti-CD3 antibodies. Non-stimulatory anti-CD3 antibodies, as used herein, encompassanti-CD3 antibodies which bind to CD3 but which: (1) only lead to low or very low signaling (i.e., T cell activation may not be fully ablated) (“minimally activating anti- CD3 antibodies”); (2) have no or limited effect on one or more of T cell functions, reactions, or properties (“non-activating anti-CD3 antibodies”); and / or (3) reverse, reduce, or block T cell stimulation and / or activation (“anti-activation anti-CD3 antibodies”).

[0291] Binding of a minimally activating anti-CD3 antibody to a T cell may only induce minimal changes in the T cell or one or more properties thereof. Binding of a non-activating anti-CD3 antibody to a T cell may not cause changes or detectable changes or may only cause negligible changes in the T cell or one or more properties thereof. Binding of an anti- activation anti-CD3 antibody may fully or partially reverse or reduce one or more changes occurred in association with T cell activation or fully or partially block or prevent one or more changes that would occur in association with T cell activation.

[0292] In some instances, the changes may be changes relating to, mediated, or caused by T cell activation. Such changes may for example be one or more of T cell functions, reactions, or properties, including: TCR conformation, interactions, or receptor-mediated events (e.g., internalization, intracellular phosphorylation, protein recruitment, signal transduction, protein expression, and / or gene expression); an increase in production and / or secretion of one or more cytokines and / or other cytotoxic and / or inflammatory molecules, such as but not limited to IL-2, IL-6, IL-7, IL-15, IFN-γ, TNF-α, GM-CSF, TSLP, perforin, and / or granzyme (e.g., 84 Attorney Docket No.: 1160430.004613 granzyme B), by the T cell; and / or cell surface expression of one or more T cell activation markers, such as but not limited to CD69, CD44, CD25, CD38, CD45RO, HLA-DR, CD40L, FasL, CXCR3, and / or CCR5.

[0293] In some cases, the phrase “minimal changes” may for example be between about 50% and about 5%, between about 45% and about 5%, between about 40% and about 5%, between about 35% and about 5%, between about 30% and about 5%, between about 25% and about 5%, between about 20% and about 5%, between about 15% and about 5%, between about 10% and about 5%, about 50%, about 45% about 40%, about 35%, about 30%, about 20%, about 10%, or about 5%, relative to a corresponding change that would occur in association with full T cell activation (e.g., compared to changes observed in fully activated T cell). In some cases, “minimal changes” in a T cell property may for example correspond to about 50% to about 5%, about 45% to about 5%, about 40% to about 5%, about 35% to about 5%, about 30% to about 5%, about 25% to about 5%, about 20% to about 5%, about 15% to about 5%, about 10% to about 5%, 50%, about 45% about 40%, about 35%, about 30%, about 20%, about 10%, or about 5% of the corresponding T cell property observed without the anti-CD3 antibody.

[0294] In some cases, the phrase “no or limited effect,” “not cause changes or detectable changes,” or “only cause negligible changes” may for example be within about +5% to about -5%, within about +3% to about -3%, within about +2% to about -2%, within about +1% to about -1%, or about 0%, relative to a corresponding change that would occur in association with full T cell activation (e.g., compared to changes observed in fully activated T cell). In some cases, the phrase “no or limited effect,” “not cause changes or detectable changes,” or “only cause negligible changes” in a T cell property may for example mean that there is no change or the change (if any) is undetectably small or within about +5% to about -5%, within about +3% to about -3%, within about +2% to about -2%, or within about +1% to about -1% of the corresponding property observed without the anti-CD3 antibody.

[0295] In some cases, the phrase “reverse, reduce, or block” T cell stimulation and / or activation may mean that changes in one or more T cell properties caused by or in association with T cell activation may be fully or partially, e.g., by about 95%, about 90%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 10% or about 5%, reversed or reduced, or that changes in one or more T cell properties to be caused (or typically caused) by or in association with T cell activation is fully (i.e., about 100%) or partially, e.g., by about 85 Attorney Docket No.: 1160430.004613 95%, about 90%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 10% or about 5%, blocked, inhibited, or prevented.

[0296] In some embodiments, an anti-CD3 antibody of the present disclosure may be a non- stimulatory anti-CD3 antibody which only minimally activates T cells.

[0297] In certain embodiments, non-stimulatory anti-CD3 antibodies may bind CD3 on T cells but only minimally cause one or more changes to TCR confirmation, interactions, or receptor-mediated events (e.g., internalization, intracellular phosphorylation, protein recruitment, signal transduction, protein expression, and / or gene expression).

[0298] In certain embodiments, non-stimulatory anti-CD3 antibodies may bind T cells, while only minimally causing increased production and / or secretion of cytokines and / or other cytotoxic and / or inflammatory molecules, such as but not limited to IL-2, IL-6, IL-7, IL-15, IFN-γ, TNF-α, GM-CSF, TSLP, perforin, and / or granzyme (e.g., granzyme B), by the T cells.

[0299] In particular embodiments, a non-stimulatory anti-CD3 antibody may bind a T cell, while only minimally causing increased production and / or secretion of IL-2 by the T cell.

[0300] In certain embodiments, non-stimulatory anti-CD3 antibodies may bind T cells while only minimally causing increased cell surface expression of one or more T cell activation markers, such as but not limited to CD69, CD44, CD25, CD38, CD45RO, HLA-DR, CD40L, FasL, CXCR3, and / or CCR5.

[0301] In particular embodiments, a non-stimulatory anti-CD3 antibody may bind a T cell without causing increased cell surface expression of CD69 in the T cell.

[0302] In further embodiments, a non-stimulatory anti-CD3 antibody may bind a T cell, while only minimally causing (i) increased production and / or secretion of cytokines and / or other cytotoxic and / or inflammatory molecules (such as but not limited to those disclosed herein) and (ii) increased cell surface expression of one or more T cell activation markers (such as but not limited to those disclosed herein).

[0303] In particular cases, a non-stimulatory anti-CD3 antibody may bind a T cell, while only minimally causing (i) increased production and / or secretion of IL-2 and (ii) increased cell surface expression of CD69.

[0304] In some embodiments, an anti-CD3 antibody of the present disclosure may be a non- stimulatory anti-CD3 antibody which does not activate T cells. 86 Attorney Docket No.: 1160430.004613

[0305]

[0306] In certain embodiments, non-stimulatory anti-CD3 antibodies may bind CD3 on T cells without causing one or more changes to TCR confirmation, interactions, or receptor- mediated events (e.g., internalization, intracellular phosphorylation, protein recruitment, signal transduction, protein expression, and / or gene expression). In certain embodiments, non-stimulatory anti-CD3 antibodies may bind T cells without causing increased production and / or secretion of cytokines and / or other cytotoxic and / or inflammatory molecules, such as but not limited to IL-2, IL-6, IL-7, IL-15, IFN-γ, TNF-α, GM-CSF, TSLP, perforin, and / or granzyme (e.g., granzyme B), by the T cells.

[0307] In particular embodiments, a non-stimulatory anti-CD3 antibody may bind a T cell without causing increased production and / or secretion of IL-2 by the T cell.

[0308] In certain embodiments, non-stimulatory anti-CD3 antibodies may bind T cells without causing increased cell surface expression of one or more T cell activation markers, such as but not limited to CD69, CD44, CD25, CD38, CD45RO, HLA-DR, CD40L, FasL, CXCR3, and / or CCR5.

[0309] In particular embodiments, a non-stimulatory anti-CD3 antibody may bind a T cell without causing increased cell surface expression of CD69 in the T cell.

[0310] In further embodiments, a non-stimulatory anti-CD3 antibody may bind a T cell without causing (i) increased production and / or secretion of cytokines and / or other cytotoxic and / or inflammatory molecules (such as but not limited to those disclosed herein) and (ii) increased cell surface expression of one or more T cell activation markers (such as but not limited to those disclosed herein).

[0311] In particular cases, a non-stimulatory anti-CD3 antibody may bind a T cell without causing increased production and / or secretion of IL-2 and without causing increased cell surface expression of CD69.

[0312] In some embodiments, an anti-CD3 antibody of the present disclosure may be non- stimulatory anti-CD3 antibody which fully or partially reverses, reduces, or blocks T cell activation.

[0313] In certain embodiments, non-stimulatory anti-CD3 antibodies may bind CD3 on T cells and reverse, prevent, block, or inhibit one or more features associated with T cell activation. 87 Attorney Docket No.: 1160430.004613

[0314] In certain embodiments, non-stimulatory anti-CD3 antibodies may bind T cells and reduce or eliminate production and / or secretion of cytokines and / or other cytotoxic and / or inflammatory molecules (such as but not limited to those disclosed herein) induced by or in association with T cell activation.

[0315] In particular embodiments, a non-stimulatory anti-CD3 antibody may bind a T cell and reduce or eliminate production and / or secretion of IL-2 by the T cell induced by or in association with T cell activation.

[0316] In certain embodiments, non-stimulatory anti-CD3 antibodies may bind T cells and reduce or eliminate cell surface expression or upregulation of one or more T cell activation markers (such as but not limited to those disclosed herein) induced by or in association with T cell activation.

[0317] In particular embodiments, a non-stimulatory anti-CD3 antibody may bind a T cell and reduce or eliminate cell surface expression or upregulation of CD69 in the T cell induced by or in association with T cell activation.

[0318] In further embodiments, a non-stimulatory anti-CD3 antibody may bind a T cell and (i) reduce or eliminate production and / or secretion of cytokines and / or other cytotoxic and / or inflammatory molecules (such as but not limited to those disclosed herein) induced by or in association with T cell activation and (ii) reduce or eliminate cell surface expression or upregulation of one or more T cell activation markers (such as but not limited to those disclosed herein) induced by or in association with T cell activation.

[0319] In particular cases, a non-stimulatory anti-CD3 antibody may bind a T cell and (i) reduce or eliminate production and / or secretion of IL-2 by the T cell induced by or in association with T cell activation and (ii) reduce or eliminate cell surface expression or upregulation of CD69 in the T cell induced by or in association with T cell activation.

[0320] Levels of cytokines and / or other cytotoxic and / or inflammatory molecules produced and / or secreted by T cells may be evaluated using any appropriate methods and techniques. In some cases, an immunoassay, such as but not limited to an enzyme-linked immunosorbent assay (ELISA) (e.g., sandwich ELISA, competitive ELISA), a radioimmunoassay (RIA), a fluoroimmunoassay (FIA), an immunofluorescence (IF) assay, a chemiluminescence immunoassays (CLIA), electrochemiluminescence detection, immunocytochemistry (ICC), immunoprecipitation (IP), western blot (WB), etc, may be used. 88 Attorney Docket No.: 1160430.004613

[0321] Changes in the level of marker expression on T cells may be evaluated using any appropriate methods and techniques. In some cases, cell staining (e.g., using an antibody specific to the marker) followed by flow cytometry may be used.

[0322] In some embodiments, non-stimulatory anti-CD3 antibodies may be used to target, identify, or select CD3-expressing cells or T cells.

[0323] In certain embodiments, such a non-stimulatory anti-CD3 antibody may be used to induce removal of CD3+ cells, such as but not limited to cancer cells of T cell lineage, e.g., cells of T cell lymphoma, peripheral T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), adult T-cell leukemia / lymphoma (ATL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), enteropathy- associated T-cell lymphoma (EATL), extranodal natural killer / T-cell lymphoma, nasal type, cutaneous T-cell lymphoma, hepatosplenic T-cell lymphoma, T-cell prolymphocytic leukemia (T-PLL), mycosis fungoides, follicular T-cell lymphoma (FTCL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), and / or lymphoblastic lymphoma. In some cases, the removal may be mediated at least partially by antibody-dependent cellular cytotoxicity (ADCC) and / or antibody-dependent cellular phagocytosis (ADCP). In some cases, the antibody may be conjugated to a cytotoxic agent and the removal may be mediated at least partially by cytotoxicity of the cytotoxic agent. Without wishing to be bound by theory, the non-activating feature of the anti-CD3 antibody may help reduce the risk of activating and / or promoting proliferation of the cancer cells.

[0324] In certain embodiments, a non-stimulatory anti-CD3 antibody may be used to identify or quantify cancer cells of T cell lineage, such as but not limited to any of those disclosed herein. Without wishing to be bound by theory, the non-activating feature of the anti-CD3 antibody may facilitate the identification or quantification without activating and / or promoting proliferation of the cancer cells.

[0325] In certain embodiments, a non-stimulatory anti-CD3 antibody may be used to select CD3+ cells for preparing cells for cell therapy. Cells for cell therapy may be for administration to a patient, and without wishing to be bound by theory, the non-activating feature of the anti-CD3 antibody may aid in preparing a population of CD3+ cells (e.g., T cells) showing a phenotype of interest. For example, excess T cell activation results in exhaustion, and the use of a non-stimulatory anti-CD3 antibody for selection may result in T 89 Attorney Docket No.: 1160430.004613 cells showing a less exhausted and / or more memory-like phenotype, which may for instance extend persistence of cells upon administration.

[0326] In some embodiments, non-stimulatory anti-CD3 antibodies may be used to prevent T cell activation or to block or suppress activated T cells.

[0327] In certain embodiments, such a non-stimulatory anti-CD3 antibody may be used to reduce, suppress, block, or prevent activities of T cells associated with an autoimmune and / or inflammatory disease, such but not limited to type I diabetes, psoriasis, scleroderma, multiple sclerosis, autoimmune cytopenias, rheumatoid arthritis, autoimmune arthritis, celiac disease, Graves’ disease, autoimmune encephalomyelitis, idiopathic uveitis, birdshot retinochoroidopathy, sympathetic ophthalmia, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, pemphigus vulgaris, Sjogren’s syndrome, Addison’s disease, Behcet’s disease, Schmidt syndrome, dermatomyositis, autoimmune vitiligo, Hashimoto thyroiditis, Kawasaki disease, pernicious anemia, autoimmune vasculitis, or fibrosis.

[0328] In some embodiments, a non-stimulatory anti-CD3 antibody according to the present disclosure may comprise a VH comprising a CDRH1, a CDRH2, and a CDRH3. Optionally a VL may be further comprised. In certain embodiments, the CDRH1, the CDRH2, and the CDRH3 may comprise or consist of the CDR1, 2, and 3 sequences, respectively, contained in any of the VHH sequences of Table 24A. In certain embodiments, the CDRH1, the CDRH2, and the CDRH3 may comprise the CDR1, 2, and 3 sequences, respectively, of an anti-CD3 antibody as shown in Table 24B. In particular embodiments, the VH may comprise or consist of a VHH sequence disclosed in Table 24A or a sequence comprising at least 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identity thereto.

[0329] In some embodiments, the non-stimulatory anti-CD3 antibody may be at least partially humanized. Humanization may be performed in any appropriate manner, including but not limited to humanization disclosed herein. In certain embodiments, a non-stimulatory anti-CD3 antibody may have one or more of: a humanized FR1, a humanized FR2, a humanized FR3, and a humanized FR4 disclosed herein, optionally selected from those in Table 13C. In certain embodiments, a non-stimulatory anti-CD3 antibody may have a 90 Attorney Docket No.: 1160430.004613 combination of the FR1, the FR2, the FR3, and the FR4 of any of the humanized anti-CD3 antibodies disclosed herein, optionally selected from a FR combination listed in Table 13C. Humanized antibodies and chimeric antibodies

[0330] In some embodiments, an antibody comprising a CD3-binding domain according to the present disclosure may be a humanized antibody or a chimeric antibody.

[0331] A “chimeric antibody” is an antibody comprising variable domain sequences of one species and constant domain sequences of another species. In some embodiments, an antibody may comprise any of the anti-CD3 human variable domain sequences described herein and constant domain sequences of a non-human species.

[0332] A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody- encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.

[0333] A “humanized antibody” refers to an antibody comprising amino acid residues from non-human CDRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of or at least one, and typically two or three, variable domains, in which all or substantially all of the (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. In some cases, FR sequences may be humanized except at given FR amino acid positions (e.g., except at 1, 2, 3, 4, 5, 6, 7, or 8 FR amino acid positions). In certain cases, at those given FR positions, the amino acid(s) derived from a FR sequence of the non- human species which the CDRs are derived from may be maintained (e.g., when CDRs are derived from llama, the humanized FR sequence may maintain the amino acid(s) found in llama VHHs at the given FR position(s). A humanized antibody optionally may further comprise at least a portion of an antibody constant domain or region derived from a human antibody. A humanized form of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0334] A “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 91 Attorney Docket No.: 1160430.004613 Fifth Edition, NIH Publication 91-3242, Bethesda Md. (1991), vols.1-3. In one embodiment, for the VL, the subgroup is subgroup kappa I as in Kabat et al., supra. In one embodiment, for the VH, the subgroup is subgroup III as in Kabat et al., supra.

[0335] Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci.13:1619-1633 (2008), and are further described, e.g., in Reichmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Natl Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos.5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol.28:489-498 (1991) (describing “resurfacing”); Dall′Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling).

[0336] Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol.151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci.13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem.272:10678-10684 (1997) and Rosok et al., J. Biol. Chem.271:22611-22618 (1996)).

[0337] The VH sequences listed in Tables 1A and 24A herein are derived from llama. Such llama antibodies may be humanized using any appropriate methods, including methods standard in the art, such as but not limited to simple embedding of CDRs into human FRs derived from one or more human germline encoded FR sequences, and / or use of the “best-fit” method. In some cases, FRs may be selected using a synthetic humanized llama nanobody library. In some cases, any available software such as but not limited to the Llamanade may be used. Certain prediction and / or actual measurement of production yields (e.g., the HADDOCK software), binding kinetics, developability parameters, such as stability, immunogenicity, T20 score indicating “humanness” of VHH, etc may also be used in combination. See e.g., Jespers et al., J Mol Biol.2004 Apr 2;337(4):893-903.; Vincke et al., J Biol Chem.2009 Jan 30;284(5):3273-3284. Soler et al, Biomolecules.2021 Jan 92 Attorney Docket No.: 1160430.004613 26;11(2):163., Sang et al., Version 1. bioRxiv. Preprint.2021 Aug 4., WO2023044272, Ramon et al., Nature Machine Intelligence volume 6, pages74–91 (2024), Moutel et al., Elife. 2016 Jul 19:5:e16228. Suela. Methods Mol Biol.2022:2446:299-312, Rossotti et al., FEBS J. 2022 Jul;289(14):4304-4327.; Martins et al., Int J Mol Sci.2023 Sep 26;24(19):14586. Gao et al., BMC Biotechnol.2013;13:55, the contents of each of which are herein incorporated by reference in their entirety. Exemplary humanized VH sequences according to the present disclosure may be found in Table 13A.

[0338] In some embodiments, a set of heavy chain CDRs of an anti-CD3 antibody as disclosed in Table 1B or 24B or herein may simply be embedded into human heavy chain FRs.

[0339] In certain embodiments, heavy chain FR sequences encoded by the VH1-02, VH1- 03, VH1-18, VH1-69, VH2-05, VH3-07, VH3-09, VH3-11, VH3-21, VH3-23, VH3-30, VH3-33, VH3-48, VH3-49, VH3-66, VH3-72, VH4-0B, VH4-31, VH4-34, VH4-39, VH4- 4A, VH4-4B, VH4-59, VH5-51, VH1-46 germline may be used. In certain embodiments, heavy chain FR sequences encoded by the VH1-03, VH1-69, VH2-05, VH3-09, VH3-23, VH4-31, VH4-39, VH4-4A, VH4-59, VH1-02, VH4-0B, VH4-59, VH1-18, or VH3-48 germline may be used. In certain embodiments, heavy chain FR sequences encoded by the VH3-23 germline may be used.

[0340] In certain embodiments, such FR sequences may be further modified to introduce one or more amino acid changes, for example to retain some of the conformation of the parent (i.e., before humanization) antibody’s antigen-binding site and / or to improve developability of the antibody.

[0341] In some embodiments, an amino acid at one or more positions within the FR sequences in a VH disclosed in Table 1A or 24A herein may be altered for humanization, e.g., substituted to another amino acid, to mimic a human antibody.

[0342] Camelid VHH and human VH sequences (e.g., the VH3-23 germline sequence) are relatively similar in the FR1, FR3, and FR4 among the four FRs. Therefore, in certain embodiments, the FR1, FR3, and FR4 sequences (e.g., the FR1, FR3, and FR4 sequences of the VH3-23 germline) may not be altered or minimally altered (e.g., via conservative amino acid substitutions; and / or by one, two, three, or four amino acids per FR) during humanization. In some cases, two, three, or four amino acids may be altered in the FR1. In some cases, one, two, three, or four amino acids may be altered in the FR2. In some cases, one amino acid may be altered in the FR4. In contrast, camelid VHH and human VH 93 Attorney Docket No.: 1160430.004613 sequences generally differ markedly in the FR2 among the four FRs. This difference, in part, relates to greater solvent exposure of these residues (where unpaired with a VL) in VHHs. Therefore, in certain embodiments, the FR2 sequence may be altered, perhaps significantly altered (e.g., via non-conservative amino acid substitutions; and / or by more than one, more than two, more than three, more than four, more than five, more than six, more than seven, or more amino acids per FR).

[0343] When camelid VHH and human VH sequences are compared, the sequence differences are often observed at particular positions, which may be referred to as hotspot residues / positions. In some cases, exemplary sequence differences at hotspot residues (from camelid VHH to human VH) may include or may be one or more of: A14P, R27F in FR1; F / Y37V, E44G, R45L, F / L47W in FR2; V75L, K83R, P84A, A94R / K in FR3; and Q108L in FR4 (Martin numbering). Therefore, in certain embodiments, one or more of such amino acid changes or one or more changes at one or more of those hotspot positions may be incorporated during humanization.

[0344] Such differences in the FR2 may particularly involve physiochemical changes (e.g., hydrophobicity, hydrophilicity, size, etc). Particularly, F / Y37V, E44G, and / or R45L (according to Martin numbering or Kabat numbering) may reduce local hydrophilicity of Nbs, which perhaps may impact antigen binding characteristics. Therefore, humanization at one or more of these positions may need particular caution, and several different amino acid change combinations at these positions may be contemplated.

[0345] In some cases, a humanized VHH sequence may comprise FR sequences derived from human FR sequences (e.g., human VH3-23 germline FR sequences) but may comprise one or more amino acid residues of camelid in the FR2. In certain cases, a humanized VHH sequence may comprise FR sequences derived from human FR sequences but may comprise a camelid residue at one or more positions 37, 44, and / or 45 (i.e., F / Y37, E44, and / or R45) according to Martin numbering or Kabat numbering (or positions 42, 49, and / or 50 (i.e., F / Y42, E49, and / or R50) according to IMGT numbering) in the FR2. In particular cases, a humanized VHH sequence may comprise FR sequences derived from human FR sequences but may comprise a camelid residue at positions 37, 44, and 45 (i.e., F / Y37, E44, and R45) according to Martin numbering or Kabat numbering (or positions 42, 49, and 50 (i.e., F / Y42, E49, and R50) according to IMGT numbering) in the FR2. In further particular cases, a humanized VHH sequence may comprise human FR sequences (FR1, FR2, FR3, and FR4) except for comprising F / Y37, E44, and R45 according to Martin numbering or Kabat numbering (or except for F / Y42, E49, and R50 according to IMGT numbering). Without 94 Attorney Docket No.: 1160430.004613 wishing to be bound by a theory, comprising one or more of F / Y37, E44, and R45 according to Martin numbering or Kabat numbering (or F / Y42, E49, and R50 according to IMGT numbering) may help retain solubility, and thus such humanized sequence may be particularly used when the antibody according to the present disclosure has the VHH format or HCAb format, or any other format wherein a VL is not paired to the anti-CD3 VHH. Exemplary humanized FR sequences include but are not limited to those listed in Table 13C.

[0346] When camelid VHH and human VH sequences are analyzed, certain amino acids are particularly found at certain FR positions.

[0347] In case of human FR sequences, the following amino acids tend to be particularly observed: E or Q at position 1; V or L at position 5; L or V at position 11; Q or K at position 13; P at position 14; G or R at position 16; R at position 19; A at position 23; A at position 24; F at position 27; V at position 37; G at position 44; L at position 45; E or V at position 46; W at position 47; S or A at position 49; A or V at position 60; T at position 68; I or V at position 69; N or D at position 73; S or A at position 74; T or S at position 77; L or V at position 78; S at position 82b; R at position 83; A, V, or P at position 84; E or D at position 85; V or L at position 89; A or V at position 93; R, K, or T at position 94; and / or L, T, or M at position 108, wherein the position is according to Kabat numbering (i.e., E or Q at position 1; V or L at position 5; L or V at position 11; Q or K at position 13; P at position 14; G or R at position 16; R at position 19; A at position 23; A at position 24; F at position 27; V at position 37; G at position 44; L at position 45; E or V at position 46; W at position 47; S or A at position 49; A or V at position 60; T at position 68; I or V at position 69; N or D at position 72a; S or A at position 72b; T or S at position 74; L or V at position 75; S at position 81; R at position 83; A, V, or P at position 84; E or D at position 85; V or L at position 89; A or V at position 93; R, K, or T at position 94; and / or L, T, or M at position 108, wherein the position is according to Martin numbering, or E or Q at position 1; V or L at position 5; L or V at position 12; Q or K at position 14; P at position 15; G or R at position 17; R at position 20; A at position 24; A at position 25; F at position 28; V at position 42; G at position 49; L at position 50; E or V at position 51; W at position 52; S or A at position 54; A or V at position 68; T at position 77; I or V at position 78; N or D at position 82; S or A at position 83; T or S at position 86; L or V at position 87; S at position 93; R at position 95; A, V, or P at position 96; E or D at position 97; V or L at position 101; A or V at position 105; R, K, or T at position 106; and / or L, T, or M at position 123, wherein the position is according to IMGT numbering). Therefore, in certain embodiments, humanization of a VH listed in Table 1A or 24A may result in a VH sequence which includes a humanized residue at one or more 95 Attorney Docket No.: 1160430.004613 of the aforementioned positions and / or one or more of the aforementioned amino acids. When the parent (camelid) VH sequence did not have the same amino acid at a given position, including such amino acid represents an amino acid modification.

[0348] Amino acid residues at hotspot positions among the afore mentioned are: P at position 14; F at position 27; V at position 37; G at position 44; L at position 45; W at position 47; L at position 78; R at position 83; A at position 84; R or K at position 94; and / or L at position 108, wherein the position is according to Kabat numbering (i.e., P at position 14; F at position 27; V at position 37; G at position 44; L at position 45; W at position 47; L at position 75; R at position 83; A at position 84; R or K at position 94; and / or L at position 108, wherein the position is according to Martin numbering, or P at position 15; F at position 28; V at position 42; G at position 49; L at position 50; W at position 52; L at position 87; R at position 95; A at position 96; R or K at position 106; and / or L at position 123, wherein the position is according to IMGT numbering). Therefore, in certain embodiments, humanization of a VH listed in Table 1A or 24A may result in a VH sequence which includes a humanized residue at one or more of the aforementioned positions and / or one or more of the aforementioned amino acids. Again, when the parent (camelid) VH sequence did not have the same amino acid at a given position, including such amino acid represents an amino acid modification. In particular embodiments, a VH may be humanized while maintaining the following llama amino acids: E or Q at position 44 and / or R at position 45 according to Kabat or Martin numbering, or E or Q at position 49 and / or R at position 50 according to IMGT numbering.

[0349] Accordingly, VH sequences obtained by humanization of any of the VH sequences of Table 1A or 24A are encompassed herein, including the humanized VH sequences which incorporate any one or more of the humanized residues disclosed above or herein.

[0350] In some cases, a humanized VH may comprise the CDRs of Antibody No.21 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in humanized Antibody No. 21 such as SEQ ID NOS: 9411, 9413, 9415, and 9417 with variations at X positions as shown in Table 13C.

[0351] In particular cases, X1 is E; X2 is V; X3 is E; X4 is G; X5 is G; X6 is L; X7 is V; X8 is Q; X9 is P; X10 is G; X11 is L; X12 is R; X13 is L; and / or X14 is A in SEQ ID NO: 9411. In particular cases, X1 is Y; X2 is Q; X3 is A; X4 is K; X5 is L; X6 is V; and / or X7 is S in SEQ ID NO: 9413. In particular cases, X1 is F; X2 is T ; X3 is S; X4 is R; X5 is N; X6 is S; X7 is K; X8 is N; X9 is T; X10 is L; X11 is L; X12 is Q; X13 is M; X14 is N; X15 is R; 96 Attorney Docket No.: 1160430.004613 X16 is A; and / or X17 is Y in SEQ ID NO: 9415. In particular cases, X1 is L in SEQ ID NO: 9417.

[0352] In certain cases, a humanized VH may comprise the CDRs of Antibody No.21 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV3-based humanized Antibody No.21 such as SEQ ID NOS: 9421, 9413, 9425, and 9427 with variations at X positions as shown in Table 13C.

[0353] In particular cases, X1 is V; and X2 is G in SEQ ID NO: 9421. In particular cases, X1 is Y; X2 is L; and / or X3 is S in SEQ ID NO: 9413. In particular cases, X1 is S; X2 is K; X3 is T; X4 is L; and / or X5 is Y in SEQ ID NO: 9425. In particular cases, the FR4 has SEQ ID NO: 9427.

[0354] In certain cases, a humanized VH may comprise the CDRs of Antibody No.21 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV1-based humanized Antibody No.21 such as SEQ ID NOS: 9431, 9433, 9435, and 9337 with variations at X positions as shown in Table 13C.

[0355] In some cases, a humanized VH may comprise the CDRs of Antibody No.4 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in humanized Antibody No.4 such as SEQ ID NOS: 9511, 9513, 9515, and 9517 with variations at X positions as shown in Table 13C.

[0356] In particular cases, X1 is E; X2 is L; X3 is E; X4 is G; X5 is G; X6 is G; X7 is L; X8 is V; X9 is Q; X10 is G; X11 is L; X12 is R; X13 is L; X14 is A; and / or X15 is A in SEQ ID NO: 9511. In particular cases, X1 is F; X2 is K; X3 is F; X4 is V; and / or X5 is A in SEQ ID NO: 9513. In particular cases, X1 is F; X2 is S; X3 is R; X4 is N; X5 is S; X6 is K; X7 is S; X8 is T; X9 is V; X10 is L; X11 is Q; X12 is M; X13 is N; X14 is S; X15 is R; and / or X16 is A in SEQ ID NO: 9515. In particular cases, X1 is L; and / or X2 is S in SEQ ID NO: 9517.

[0357] In certain cases, a humanized VH may comprise the CDRs of Antibody No.4 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV3-based humanized Antibody No.4 such as SEQ ID NOS: 9521, 9523, 9525, and 9527 with variations at X positions as shown in Table 13C.

[0358] In particular cases, X1 is E; X2 is L; X3 is Q; and / or X4 is A in SEQ ID NO: 9521. In particular cases, X1 is F; X2 is F; and / or X3 is A in SEQ ID NO: 9523. In particular cases, X1 is A or S; X2 is S; X3 is T; and / or X4 is V in SEQ ID NO: 9525. In particular cases, in SEQ ID NO: 9527. Among such cases, in some instances, X1 is E or Q, X2 is V or L, X3 is K or Q, and / or X4 is G or A in SEQ ID NO: 9521; and / or X1 is A or S; X2 is N; X3 is S or T; and X4 is L in SEQ ID NO: 9525. 97 Attorney Docket No.: 1160430.004613

[0359] In certain cases, a humanized VH may comprise the CDRs of Antibody No.4 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV1-based humanized Antibody No.4such as SEQ ID NOS: 9531, 9533, 9535, and 9537 with variations at X positions as shown in Table 13C.

[0360] In some cases, a humanized VH may comprise the CDRs of Antibody No.14 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in humanized Antibody No. 14 such as SEQ ID NOS: 9611, 9613, 9615, and 9617 with variations at X positions as shown in Table 13C.

[0361] In particular cases, X1 is E; X2 is Q; X3 is L; X4 is E; X5 is G; X6 is G; X7 is L; X8 is V; X9 is Q; X10 is P; X11 is G; X12 is L or V; X13 is R; X14 is L; and / or X15 is A in SEQ ID NO: 9611. In particular cases, X1 is Y; X2 is K; X3 is E; X4 is F; X5 is V; and / or X6 is S in SEQ ID NO: 9613. In particular cases, X1 is F; X2 is S; X3 is R; X4 is N; X5 is S; X6 is K; X7 is N; X8 is T; X9 is V; X10 is L; X11 is Q; X12 is M; X13 is N; X14 is R; and / or X15 is A in SEQ ID NO: 9615. In particular cases, X1 is L in SEQ ID NO: 9617.

[0362] In certain cases, a humanized VH may comprise the CDRs of Antibody No.14 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV3-based humanized Antibody No.14 such as SEQ ID NOS: 9621, 9623, 9625, and 9627 with variations at X positions as shown in Table 13C.

[0363] In particular cases, X1 is E; X2 is L; X3 is Q; and / or X4 is G in SEQ ID NO: 9621. In particular cases, X1 is Y; X2 is E; X3 is F; and / or X4 is S in SEQ ID NOS: 9623. In particular cases, X1 is S; X2 is T; X3 is V; X4 is R; and / or X5 is A in SEQ ID NOS: 9625. In particular cases, the FR4 comprises SEQ ID NOS: 9627.

[0364] Among such cases, in some instances, X1 is Q or E; X2 is V or L; X3 is K or Q; and X4 is G in SEQ ID NO: 9621; X1 is Y; X2 is D or E; X3 is F; and X4 is A or S in SEQ ID NO: 9623; and / or X1 is A; X2 is S or T; X3 is V or L; X4 is R; and X5 is A in SEQ ID NO: 9625.

[0365] In certain cases, a humanized VH may comprise the CDRs of Antibody No.14 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV1-based humanized Antibody No.14 such as SEQ ID NOS: 9631, 9633, 9635, and 9637 with variations at X positions as shown in Table 13C.

[0366] In some cases, a humanized VH may comprise the CDRs of Antibody No.15 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in humanized Antibody No. 15 such as SEQ ID NOS: 9711, 9713, 9715, and 9717 with variations at X positions as shown in Table 13C. 98 Attorney Docket No.: 1160430.004613

[0367] In particular cases, X1 is E; X2 is L; X3 is E; X4 is G; X5 is G; X6 is L; X7 is V; X8 is Q; X9 is G; X10 is L; X11 is R; X12 is L; and / or X13 is A in SEQ ID NO: 9711. In particular cases, X1 is F; X2 is K; X3 is V; and / or X4 is S in SEQ ID NO: 9713. In particular cases, X1 is F; X2 is S; X3 is R; X4 is N; X5 is S; X6 is K; X7 is N; X8 is T; X9 is V; X10 is L; X11 is Q; X12 is M; X13 is N; X14 is R; X15 is A; and / or X16 is V in SEQ ID NO: 9715. In particular cases, X1 is L in SEQ ID NO: 9717.

[0368] In certain cases, a humanized VH may comprise the CDRs of Antibody No.15 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV3-based humanized Antibody No.15 such as SEQ ID NOS: 9721, 9723, 9725, and 9727 with variations at X positions as shown in Table 13C.

[0369] In particular cases, X1 is L; and / or X2 is G in SEQ ID NO: 9721. In particular cases, X1 is F; and / or X2 is S in SEQ ID NO: 9723. In particular cases, X1 is S; X2 is K; X3 is N; X4 is T; X5 is V; and / or X6 is A in SEQ ID NO: 9725. In particular cases, the FR4 comprises SEQ ID NO: 9727.

[0370] Among such cases, in some instances, X2 is S or A in SEQ ID NO: 9723; X3 is N or T and X5 is V or L in SEQ ID NO: 9725.

[0371] In certain cases, a humanized VH may comprise the CDRs of Antibody No.15 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV1-based humanized Antibody No.15 such as SEQ ID NOS: 9731, 9733, 9735, and 9737 with variations at X positions as shown in Table 13C.

[0372] In some cases, a humanized VH may comprise the CDRs of Antibody No.19 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in humanized Antibody No. 19 such as SEQ ID NOS: 9811, 9813, 9815, and 9817 with variations at X positions as shown in Table 13C.

[0373] In particular cases, X1 is E; X2 is L; X3 is E; X4 is G; X5 is G; X6 is L; X7 is V; X8 is Q; X9 is P; X10 is G; X11 is L; X12 is R; X13 is L; and / or X14 is A in SEQ ID NO: 9811. In particular cases, X1 is F; X2 is K; X3 is V; and / or X4 is A in SEQ ID NO: 9813. In particular cases, X1 is F; X2 is S; X3 is R; X4 is N; X5 is A; X6 is K; X7 is K; X8 is T; X9 is V; X10 is L; X11 is Q; X12 is M; X13 is N; X14 is R; X15 is A; and / or X16 is V in SEQ ID NO: 9815. In particular cases, X1 is L in SEQ ID NO: 9817.

[0374] In certain cases, a humanized VH may comprise the CDRs of Antibody No.19 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV3-based humanized Antibody No.19 such as SEQ ID NOS: 9821, 9823, 9825, and 9827 with variations at X positions as shown in Table 13C. 99 Attorney Docket No.: 1160430.004613

[0375] In particular cases, X1 is L; and / or X2 is G in SEQ ID NO: 9821. In particular cases, X1 is F; and / or X2 is A in SEQ ID NO: 9823. In particular cases, X1 is A; X2 is K; X3 is T; X4 is V; X5 is R; X6 is A; and / or X7 is V in SEQ ID NO: 9825. In particular cases, X1 is L in SEQ ID NO: 9827.

[0376] Among such cases, in some instances, X1 is V in SEQ ID NO: 9821; and / or X3 is S in SEQ ID NO: 9825.

[0377] In certain cases, a humanized VH may comprise the CDRs of Antibody No.19 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV1-based humanized Antibody No.19 such as SEQ ID NOS: 9831, 9833, 9835, and 9837 with variations at X positions as shown in Table 13C.

[0378] In some cases, a humanized VH may comprise the CDRs of Antibody No.25 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in humanized Antibody No. 25 such as SEQ ID NOS: 9911, 9913, 9915, and 9917 with variations at X positions as shown in Table 13C.

[0379] In particular cases, X1 is E; X2 is V; X3 is E; X4 is G; X5 is G; X6 is G; X7 is L; X8 is V; X9 is Q; X10 is P; X11 is G; X12 is L; X13 is R; X14 is L; and / or X15 is A in SEQ ID NO: 9911. In particular cases, X1 is F; X2 is K; X3 is V; and / or X4 is S in SEQ ID NO: 9913. In particular cases, X1 is F; X2 is T; X3 is S; X4 is R; X5 is N; X6 is A; X7 is K; X8 is N; X9 is S; X10 is L; X11 is L; X12 is Q; X13 is M; X14 is N; X15 is R; and / or X16 is A in SEQ ID NO: 9915. In particular cases, X1 is L in SEQ ID NO: 9917.

[0380] In certain cases, a humanized VH may comprise the CDRs of Antibody No.25 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV3-23-based humanized Antibody No.25 such as SEQ ID NOS: 9921, 9923, 9925, and 9927 with variations at X positions as shown in Table 13C.

[0381] In certain cases, a humanized VH may comprise the CDRs of Antibody No.25 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV3-based humanized Antibody No.25 such as SEQ ID NOS: 9931, 9933, 9935, and 9937 with variations at X positions as shown in Table 13C.

[0382] In particular cases, X1 is V; and / or X2 is A in SEQ ID NO: 9931. In particular cases, X1 is F; and / or X2 is S in SEQ ID NO: 9933. In particular cases, X1 is A; X2 is S; X3 is L; X4 is N; X5 is R; and / or X6 is A in SEQ ID NO: 9935. In particular cases, the FR4 may comprise SEQ ID NO: 9937.

[0383] Among such cases, in some instances, X1 is L in SEQ ID NO: 9931, X1 is S and / or X2 is T in SEQ ID NO: 9935. 100 Attorney Docket No.: 1160430.004613

[0384] In certain cases, a humanized VH may comprise the CDRs of Antibody No.25 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in IGHV1-based humanized Antibody No.25 such as SEQ ID NOS: 9941, 9943, 9945, and 9947 with variations at X positions as shown in Table 13C.

[0385] In some cases, a humanized VH may comprise the CDRs of Antibody No.21, 4, 14, 15, 19, or 25 and comprise consensus FR1, FR2, FR3, and FR4 sequences found in humanized Antibody No.21, 4, 14, 15, 19, or 25 such as SEQ ID NOS: 3901, 3903, 3905, and 3907 with variations at X positions as shown in Table 13C.

[0386] Exemplary humanized VH sequences include but are not limited to those listed in Table 13A. Further encompassed by the present disclosure include humanized VH sequences which comprise three CDRs (CDR1, CDR2, and CDR3) shown in Table 13B or 24B and four FRs (FR1, FR2, FR3, and FR4) shown in Table 13C, wherein individual CDRs may be taken from one antibody or two or more different antibodies shown in Table 13B or 24B, and individual FRs may be taken from one antibody or two or more different antibodies shown in Table 13C. In some cases, the three CDRs (CDR1, CDR2, and CDR3) may be taken from one antibody shown in Table 13B, and the four FRs (FR1, FR2, FR3, and FR4) may be taken from one antibody or two or more different antibodies shown in Table 13C. In certain cases, the three CDRs (CDR1, CDR2, and CDR3) may be taken from one antibody shown in Table 13B or 24B, and the four FRs (FR1, FR2, FR3, and FR4) may be taken from another antibody shown in Table 13C. Developability of anti-CD3 antibodies and antigen-binding fragments

[0387] Some embodiments of the disclosure may relate to anti-CD3 antibodies and antigen- binding fragments having desirable developability. Some embodiments of the disclosure may relate to anti-CD3 antibodies and antigen-binding fragments having reduced polyspecificity. Some embodiments of the disclosure may relate to anti-CD3 antibodies and antigen-binding fragments having reduced tendency of self-interaction. Some embodiments of the disclosure may relate to anti-CD3 antibodies and antigen-binding fragments having improved tolerance to low pH stress. Some embodiments of the disclosure may relate to anti-CD3 antibodies and antigen-binding fragments having reduced propensity to aggregate or multimerize. Some embodiments of the disclosure may relate to anti-CD3 antibodies and antigen-binding fragments having improved binding to target cells (CD3-expressing cells). Some embodiments of the disclosure may relate to anti-CD3 antibodies and antigen-binding fragments having increased binding preference at an acidic pH. Some embodiments of the 101 Attorney Docket No.: 1160430.004613 disclosure may relate to anti-CD3 antibodies and antigen-binding fragments having improved cytokine release syndrome (CRS) risk profiles, in some instances due to pH- dependent antigen binding profiles.

[0388] The term “developable” or “developability” refers to the extent to which one or more polypeptides in a plurality of polypeptides possess desirable characteristics for manufacture, storage, off-target binding, etc., such as, e.g., desirable binding specificity, for example binding to a cognate antigen at desirable affinity and not significantly to non-cognate antigens; desirable expression, for example, in mammalian cells; solubility; viscosity; aggregation; chemical and / or physical stability; desirable shelf-life; melting temperature; pharmacokinetic profiles; circulation half-life; and clearance characteristics. Such characteristics may serve as indicia, independently, as combinations of sub-sets of such indicia, or in totality, for the likelihood that such one or more polypeptides may be successfully developed as a therapeutic candidate, and ultimately an approved drug. Generally, polypeptides with desirable developability characteristics possess one or more of relatively high solubility, relatively low viscosity, relatively low propensity for aggregation, relatively high chemical stability, relatively high physical stability, relatively long shelf life, relatively high melting temperature, relatively long circulation half-life, relatively slow rate of clearance, and the like. By contrast polypeptides with undesirable developability characteristics generally possess one or more of: relatively low solubility, relatively high viscosity, relatively high propensity for aggregation, relatively poor chemical stability, relatively poor physical stability, relatively short shelf life, relatively low melting temperature, relatively short circulation half-life, relatively fast rate of clearance, and the like.

[0389] The tendency of antibodies to bind multiple targets is referred to as “polyspecificity,” which, with target-specific therapeutic antibodies, may be associated with negative clinical outcomes. CD3 binding domains of the present disclosure may exhibit reduced polyspecificity [e.g., as assessed by interaction with polyspecific reagent (PSR)]. Such domains may be engineered from starting domains by substituting various domain amino acid residues with residues having charged side chains. Residues may be substituted with amino acid residues having negatively charged side chains, e.g., Asp and Glu residues. Residues selected for substitution may be selected from those not predicted to specifically interact with CD3 amino acid residues targeted by the CD3 binding domains.

[0390] Methods and assays that may be employed to ascertain the degree to which polypeptides, such as anti-CD3 antibodies and / or antigen-binding fragments as described 102 Attorney Docket No.: 1160430.004613 herein, possess desirable developability characteristics are available in the art, and include, one or more of; polyspecificity reagent (PSR) assays (WO 2014 / 179363 and Xu et al., Protein Eng Des Sel, Vol.26, pages 663-670 (2013)); SMP and SCP assays and the like; cross interaction chromatography (CIC); self-interaction chromatography (SIC); hydrophobic interaction chromatography (HIC); size exclusion chromatography (SEC); dynamic light scattering (DLS) spectroscopy; photon correlation spectroscopy; quasi-elastic light scattering, circular dichroism (CD), viscosity measurements; whole cell binding; tissue micro array methodologies; ELISA assays such as BVP ELISA assays; AC-SINS assays (Liu et al; MAbs, Vol.6, pages 483-492 (2014); melting temperature (Tm) assays; differential scanning calorimetry or differential scanning fluorometry (DSF); and the like (see, e.g., He et al., J. Pharm. Sci., Vol.100(4), pp.1330-1340 (2011); Wagner et al., Pharm. Develop. & Technol (posted online 2012; hyper-text transfer protocol: informahealthcare.com / doi / abs / 10.3109 / 10837450.2011.649851); Hotzel et al., MAbs, Vol. 4(6), pages 753-7601 (2012); Weiqiang et al., J. Pharm. Sci., Vol.101(5), pp.1701-1720 (2012); Banks et al., J. Pharm. Sci., Vol.101(8), pp.2720-2732 (2012); Lie et al., J. Pharm. Sci., Vol.94(9), pp.1928-1948 (2005); and Payne et al., Biopolymers, Vol.85(5), pp.527- 533 (2006)).

[0391] In some embodiments, antibodies that are identified as possessing decreased developability are so detected by virtue of their interaction with a PSR and, as such, are referred to as “polyspecific” polypeptides. Such polyspecific antibodies may be referred to as relatively “undevelopable” or relatively “non-developable.”

[0392] A “developability profile” refers to an index that may be assigned to antibodies upon assessing their developability. A developability profile is a measure or metric by which developability of anti-CD3 antibodies may be assessed, compared, and / or ranked. Such developability profiles serve as a measure of the degree of interaction of CD3 binders and antibodies comprising them. The degree of interaction may be assessed by any number of means available in the art that provides an output value that correlates with a strength or affinity of a polypeptide for a moiety to which it is bound. Exemplary means include flow cytometry means, such as fluorescence-activated cell sorting (FACS); enzyme-linked immunosorbent assay (ELISA); quantitative immunoaffinity assays or immunoprecipitation assays; mammalian two-hybrid or yeast two-hybrid assays, and the like. In the context of FACS, as demonstrated in the Examples, a degree of interaction between polypeptides in the plurality and the PSR may be ascertained by generating a mean fluorescence intensity (MFI) 103 Attorney Docket No.: 1160430.004613 for each polypeptide-PSR interaction that is detected, and then ordering the MFI in either ascending or descending order, thereby ranking the polypeptides in the plurality according to the relative degree of interaction between each detected polypeptide and the PSR. Such a ranking provides for a ranking of polypeptides of the plurality such that those polypeptides possessing enhanced developability are readily ascertained, as are those polypeptides possessing decreased developability.

[0393] A developability profile may also take the form of a normalized score, for example, by normalizing developability of anti-CD3 antibodies described herein to the developability of a standard (or control) antibody, e.g., anti-HEL antibody.

[0394] In some embodiments, anti-CD3 antibodies or antigen-binding fragment as described herein may exhibit reduced polyspecificity or tendency to bind to multiple molecules or epitopes. In some embodiments, polyspecificity may be determined based on the poly- specificity reagent (PSR) score obtained by a PSR assay. In some embodiments, PSR scores may be determined as described in Examples. In some embodiments, anti-CD3 antibodies and / or antigen-binding fragments as described herein may display a PSR score of between about 0.0 and about 0.45. In some embodiments, the PSR is between about 0.0 and about 0.4. In some embodiments, the PSR is between about 0.0 and about 0.35. In some embodiments, the PSR is between about 0.0 and about 0.3. In some embodiments, the PSR is between about 0.0 and about 0.25. In some embodiments, the PSR is between about 0.0 and about 0.2. In some embodiments, the PSR is between about 0.0 and about 0.15. In some embodiments, the PSR is between about 0.0 and about 0.1.

[0395] In some embodiments, 0.0 ≤ PSR score < 0.10 is considered as “clean PSR”. For example, Antibody Nos.2, 5, 6, 9, 11, 12, 13, 14, 19, 20, 27, 28, and 29 show a clean PSR score. Among the humanized antibodies described herein tested for a PSR score, for example, Antibody Nos.21-h1, 21-h3, 21-h4, 21-h5, 21-h6, 21-h9, 21-h11, 21-h12, 21-h15, 21-h16, 21-h19, 21-h20, 21-h25, 21-h41, 21-h42, 4-h1, 4-h2, 4-h3, 4-h4, 4-h5, 4-h6, 4-h7, 4-h8, 4-h9, 4-h10, 4-h11, 4-h12, 4-h13, 4-h14, 4-h15, 4-h16, 4-h17, 4-h19, 4-h20,4-h21, 4-h22, 4-h23, 4- h25, 4-h26, 4-h27, 4-h28, 4-h30, 4-h31, 4-h32, 4-h33, 4-h34, 14-h28, 14-h34, 14-h35, 15- h16, 15-h20, 15-h23, 15-h28, 15-h29, 19-h2, 19-h3, 19-h4, 19-h6, 19-h9, 19-h13, 19-h17, 19- h24, 19-h26, 19-h27, 19-h28, 19-h29, 19-h30, and 19-h31 show a clean PSR score. In some embodiments, 0.10 ≤ PSR score < 0.33 is considered as “low PSR”. For example, Antibody Nos.1, 3, 4, 7, 8, 10, 15, 16, 17, 18, 21, 22, 23, 24, 25, and 26 show a low PSR score. Among the humanized antibodies described herein tested for PSR score, for example, Antibody Nos. 104 Attorney Docket No.: 1160430.004613 21-h2, 21-h7, 21-h8, 21-h10, 21-h13, 21-h14, 21-h17, 21-h18, 21-h21, 21-h22, 21-h24, 21- h26, 21-h27, 21-h29, 21-h31, 21-h32, 21-h33, 21-h34, 21-h35, 21-h36, 21-h37, 21-h38, 21- h39, 21-h40, 21-h43, 21-h44, 4-h18, 4-h24, 4-h29, 14-h1, 14-h2, 14-h3, 14-h4, 14-h5, 14-h6, 14-h7, 14-h8, 14-h9, 14-h10, 14-h11, 14-h12, 14-h13, 14-h14, 14-h15, 14-h16, 14-h17, 14- h18, 14-h19, 14-h20, 14-h21, 14-h22, 14-h23, 14-h24, 14-h26, 14-h27, 14-h29, 14-h30, 14- h31, 14-h33, 14-h46, 15-h1, 15-h3, 15-h4, 15-h6, 15-h7, 15-h8, 15-h9, 15-h10, 15-h11, 15- h12, 15-h13, 15-h21, 15-h22, 15-h24, 15-h26, 15-h27, 19-h10, 19-h18, 25-h21, 25-h26, 25- h28 show a low PSR score. In some embodiments, 0.33 ≤ PSR score < 0.66 is considered as “medium PSR”. In some embodiments, 0.66 ≤ PSR score ≤ 1.00 is considered as “high PSR”. In some embodiments, a high PSR score is indicative of decreased (or poor) developability. Generally, the lower the PSR score the more favorable the developability of the antibody.

[0396] In some embodiments, anti-CD3 antibodies or antigen-binding fragment as described herein may exhibit reduced hydrophobicity. In some embodiments, hydrophobicity may be determined based on the retention time observed during HIC. In some embodiments, HIC may be performed and retention times may be obtained as described in Examples. In some embodiments, anti-CD3 antibodies or antigen-binding fragment as described herein may exhibit an HIC retention time of less than about 10.5 minutes (a clean to low HIC score). In some embodiments, anti-CD3 antibodies or antigen-binding fragment as described herein may exhibit 10.5 minutes ≤ HIC retention time < 11.5 minutes (a medium HIC score).11.5 minutes ≤ HIC retention time may be considered a high HIC score. Generally, the lower the HIC retention time the more favorable the developability of the antibody. Among the humanized antibodies described herein tested for a HIC score, for example, Antibody Nos. 21-h1, 21-h3, 21-h7, 21-h8, 21-h9, 21-h12, 21-h13, 21-h14, 21-h15, 21-h24, 21-h43, 21-h44, 4-h1, 4-h2, 4-h3, 4-h4, 4-h5, 4-h6, 4-h7, 4-h8, 4-h9, 4-h10, 4-h11, 4-h12, 4-h13, 4-h14, 4- h16, 4-h17, 4-h18, 4-h19, 4-h20, 4-h22, 4-h26, 4-h28, 4-h29, 14-h1, 14-h2, 14-h4, 14-h6, 14- h7, 14-h10, 14-h11, 14-h19, 14-h21, 14-h24, 14-h27, 14-h46, 15-h1, 15-h2, 15-h3, 15-h4, 15- h5, 15-h6, 15-h7, 15-h8, 15-h9, 15-h10, 15-h11, 15-h12, 15-h13, 15-h15, 15-h16, 15-h22, 19- h2, 19-h3, 19-h6, 19-h28, 19-h29, 25-h1, 25-h2, 25-h3, 25-h4, 25-h5, 25-h8, 25-h10, 25-h12, and 25-h17 show a clean to low HIC score.

[0397] In some embodiments, anti-CD3 antibodies or antigen-binding fragment as described herein may exhibit reduced tendency for self-interaction. In some embodiments, tendency for self-interaction may be determined based on ∆λmax values observed during affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS). In some embodiments, AC-SINS may 105 Attorney Docket No.: 1160430.004613 be performed and ∆λmax values may be obtained as described in Examples. In some embodiments, anti-CD3 antibodies and / or antigen-binding fragments as described herein may display ∆λmax of between about 0.0 nm and about 15.0 nm. In some embodiments, ∆λmax of between about 0.0 nm and about 10.0 nm. In some embodiments, ∆λmax of between about 0.0 nm and about 7.5 nm. In some embodiments, ∆λmax of between about 0.0 nm and about 5.0 nm. In some embodiments, ∆λmax of between about 0.0 nm and about 3.0 nm. In some embodiments, ∆λmax of between about 0.0 nm and about 2.0 nm. In some embodiments, ∆λmax of between about 0.0 nm and about 1.0 nm. In some embodiments, 0.0 nm ≤ ∆λmax < 5.0 nm is considered as “low self-interaction”. In some embodiments, 5.0 nm ≤ ∆λmax < 20.0 nm is considered as “medium self-interaction”. In some embodiments, 10.0 nm ≤ ∆λmax is considered as “high self-interaction”. Generally, the lower the tendency for self-interaction the more favorable the developability of the antibody.

[0398] In some embodiments, anti-CD3 antibodies or antigen-binding fragment as described herein may exhibit reduced viscosity. In some embodiments, viscosity may be determined based on diffusion interaction parameter (kD) values observed during dynamic light scattering (DLS). In some embodiments, DLS may be performed and kD values may be obtained as described in Examples, e.g., using 10 mM histidine buffer (pH about 6). In some embodiments, anti-CD3 antibodies and / or antigen-binding fragments as described herein may display kD of about 5 mL / g or higher. In some embodiments, the kD may be about 10 mL / g or higher. In some embodiments, the kD may be about 15 mL / g or higher. In some embodiments, the kD may be about 20 mL / g or higher. In some embodiments, the kD may be about 25 mL / g or higher. In some embodiments, ∆λmax < 20 mL / g may be considered to be associated with high viscosity or high opalescence. Generally, the lower the viscosity the more favorable the developability of the antibody.

[0399] In some embodiments, anti-CD3 antibodies or antigen-binding fragment as described herein may exhibit reduced chance of heavy-light chain mispairing (including failure to pair). In some embodiments, heavy-light chain mispairing may be determined based on the presence of a heavy chain peak (indicating a heavy chain which did not successfully pair with a light chain) and / or a light chain peak (indicating a light chain which did not successfully pair with a heavy chain) observed during liquid chromatography–mass spectrometry (LC- MS). In some embodiments, LC-MS may be performed as described in Examples. In some embodiments, anti-CD3 antibodies and / or antigen-binding fragments as described herein may 106 Attorney Docket No.: 1160430.004613 display no heavy chain peak or light chain peak. Generally, the smaller the heavy chain peak and light chain peak the more favorable the developability of the antibody.

[0400] In some embodiments, anti-CD3 antibodies or antigen-binding fragment as described herein may exhibit reduced propensity to aggregate. In some embodiments, propensity to aggregate may be determined based on % monomer values (i.e., % of antibody species (e.g., IgG or Fab) that are existing in its full size without aggregation or multimerization, among proteins from antibody production and optionally purification) observed during size exclusion chromatography (SEC). In some embodiments, SEC may be performed as described in Examples. In some embodiments, anti-CD3 antibodies and / or antigen-binding fragments as described herein may display % monomer in SEC of about 95% or higher, which indicates that the antibody is substantially existing as a monomer, i.e., not aggregating. In some embodiments, the % monomer may be about 97% or higher. In some embodiments, the % monomer may be about 98% or higher. In some embodiments, the % monomer may be about 99% or higher. In some embodiments, the % monomer may be about 99.5% or higher. Generally, the larger the % monomer value the more favorable the developability of the antibody.

[0401] In some embodiments, anti-CD3 antibodies or antigen-binding fragments as described herein may exhibit improved tolerance to an acidic environment or acidic stress, such as a pH of about 6 or below, about 5 or below, about 4 or below, or about 3.5 or below. In some embodiments, tolerance to low pH may be determined based on propensity to aggregate when exposed to low pH. In some embodiments, propensity to aggregate under a low pH may be determined based on % monomer values (e.g., monomer IgG or monomer Fab) observed during SEC after exposure to low pH. In some embodiments, such SEC for low pH tolerance test may be performed as described in Examples. In some embodiments, anti-CD3 antibodies and / or antigen-binding fragments as described herein may display % monomer in SEC of about 95% or higher after exposure to a low pH, which indicates that the antibody is substantially existing as a monomer, i.e., not aggregating. In some embodiments, the % monomer may be about 96% or higher. In some embodiments, the % monomer may be about 97% or higher. In some embodiments, the % monomer may be about 98% or higher. In some embodiments, the % monomer may be about 99% or higher. Generally, the larger the % monomer value after exposure to a low pH, the higher the tolerance to acidic stress, i.e., the more favorable the developability of the antibody. Without wishing to be bound by theory, 107 Attorney Docket No.: 1160430.004613 improved tolerance to acidic stress may help provide longer shelf-life and / or improved in vivo stability (e.g., in an acidic cancer microenvironment).

[0402] In some embodiments, anti-CD3 antibodies and / or antigen-binding fragments as described herein may display a Tm of about 65°C or higher. In some embodiments, Tm may be determined using DSF, which may be performed as described in Examples, or any other appropriate methods. Generally, the higher the Tm is the more stable the antibody, i.e., mode developable.

[0403] In some embodiments, anti-CD3 antibodies and / or antigen-binding fragments as described herein may be further modified to minimize effector function, e.g., a silent Fc.

[0404] The term “cytokine release syndrome” (or “CRS”) refers to a pro-inflammatory, positive feedback loop between cytokines and immune cells leading to excessive or uncontrolled release of pro-inflammatory cytokines by cells within the immune system (see, e.g., Lee et al., Blood, Vol.124, pages 188-195 (2014) and Tisoncik et al., Microbiol Mol Biol Rev, Vol.76, pages 16-32 (2012). Upon stimulation and activation, T cells release a series of cytokines to a level and degree that generates untoward biological / physiological effects or varying degree and severity, including acute inflammation characterized by, e.g., rubor (redness), swelling or edema, calor (heat), dolor (pain), and “functio laesa” (loss of function). When localized in skin or other tissue, biological / physiological effects comprise increased blood flow, enabling vascular leukocytes and plasma proteins to reach extravascular sites of injury, increasing local temperatures and generation of pain, tissue edema and extravascular pressure and a reduction in tissue perfusion. Other biological / physiological effects comprise organ and system dysfunction, such as cardiac dysfunction, adult respiratory distress syndrome, neurologic toxicity, renal and / or hepatic failure, and disseminated intravascular coagulation. Elevated levels of IFNγ, IL-6, TNFα, TGFbeta, IL-2, granulocyte macrophage–colony-stimulating factor (GM-CSF), IL-10, IL-8, IL-5, and / or fractalkine are implicated as predictive and / or causative of CRS or the propensity to elicit CRS upon T-cell stimulation.

[0405] In certain embodiments, the anti-CD3 antibodies and / or antigen-binding fragments described herein are detuned and / or modified to reduce the likelihood or severity of CRS induced by the antibody. Non-limiting exemplary modifications may include silent Fc regions (e.g., removing the Fc completely or modifying the Fc region to reduce or eliminate effector 108 Attorney Docket No.: 1160430.004613 function), and / or masking (e.g., a polypeptide mask that is positioned such that it reduces or inhibits the ability of the antibody or antigen-binding fragment to specifically bind CD3). Degradation propensity

[0406] In some embodiments, the anti-CD3 antibodies and / or antigen-binding fragments described herein, anti-CD3 ABR, and / or multi-specific antibodies may have reduced tendency / propensity to degrade.

[0407] Certain proteins, depending on the amino acid sequences, may be prone to degradation. For example, when a protein is placed in a stress condition (e.g., during prolonged storage in and / or exposure to high pH such as pH 8.0-8.5 or low pH such as pH 5.5-6.0 or high temperature such as 40℃), asparagine (Asn (N)) and aspartic acid (Asp (D)) residues, particularly when the residues are present in a degradation motif (typically defined based on two consecutive amino acids containing Asn or Asp and its adjacent amino acid in a protein sequence), often go through chemical modification via Asn deamidation and Asp isomerization, respectively. Therefore, the presence of Asn and Asp degradation motifs impacts protein stability. In case of antibodies, if a degradation motif is present in a CDR, modification of the degradation motif can also impact binding to the target by the antibody, and binding may not be achieved at a desired level.

[0408] In some embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may not contain a degradation motif “DG” (Asp-Gly) in the CDRH3. For example, the CDRH3 of each of Antibody Nos.1-30 and their humanized versions (such as but not limited to Antibody Nos. 21-h1 through 21-h44, 4-h1 through 4-h34, 14-h1 through 14-48, 15-h1 through 15-h29, 19- h1 through 19-h32, and 25-h1 through 25-h28) and Antibody Nos.31-33, 35-37, and 39-47 lacks “DG” (see e.g., Tables 1B, 13B, and 24B). In certain embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may not have a degradation motif “DG” in the heavy chain CDRs. For example, the heavy chain CDRs of each of Antibody Nos.1-25 and 27-30 and their humanized versions (such as but not limited to Antibody Nos.21-h1 through 21-h44, 4-h1 through 4-h34, 14-h1 through 14-48, 15-h1 through 15-h29, 19-h1 through 19-h32, and 25-h1 through 25-h28), and Antibody Nos.31-33, 35-37, and 39-47 lack “DG” (see e.g., Tables 1B, 13B, and 24B). In particular embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi- specific antibody containing an anti-CD3 ABR) according to the disclosure may not contain a degradation motif “DG” in the CDRs. For example, the CDRs of each of Antibody Nos.1-25 109 Attorney Docket No.: 1160430.004613 and 27-30 and their humanized versions (such as but not limited to Antibody Nos.21-h1 through 21-h44, 4-h1 through 4-h34, 14-h1 through 14-48, 15-h1 through 15-h29, 19-h1 through 19-h32, and 25-h1 through 25-h28) and Antibody Nos.31-33, 35-37, and 39-47 lack “DG” (see e.g., Tables 1B, 13B, and 24B).

[0409] Exemplary degradation motifs containing Asn include NG (generally highest modification rates among Asn degradation motifs), NH, NS, NN, NT, NQ, NF, NW, and NY, and exemplary degradation motifs containing Asp include DG (generally highest modification rates among Asp degradation motifs), DS, DD, DN, DR, and DY. In some embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of one or more of such degradation motifs in the CDRs. In certain embodiments, an anti-CD3 antibody or anti- CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of one or more of such degradation motifs in the VH. In certain embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of one or more of such degradation motifs in the VH and (if present) VL. In particular embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may lack NG and / or DG in the CDRH3. For example, the CDRH3 of each of Antibody Nos.1-30 and their humanized versions (such as but not limited to Antibody Nos.21-h1 through 21-h44, 4-h1 through 4-h34, 14-h1 through 14-48, 15-h1 through 15-h29, 19-h1 through 19-h32, and 25-h1 through 25-h28) and Antibody Nos.33, 35-37, and 39-47 lacks “NG” and “DG” (see e.g., Tables 1B, 13B, and 24B). In particular embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may lack NG and / or DG in the CDRs. In particular embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi- specific antibody containing an anti-CD3 ABR) according to the disclosure may lack both NG and DG in the CDRs. For example, the CDRs of each of Antibody Nos.1-25, 27-28, and 30 and their humanized versions (such as but not limited to Antibody Nos.21-h1 through 21- h44, 4-h1 through 4-h34, 14-h1 through 14-48, 15-h1 through 15-h29, 19-h1 through 19-h32, and 25-h1 through 25-h28) and Antibody Nos.33, 35-37, and 39-47 lack “NG” and “DG” (see e.g., Tables 1B, 13B, and 24B).

[0410] It has been reported that, in case of antibodies, different degradation motifs are modified at different rates depending on which CDR the motif is in. For example, according to Lu X et al (see e.g., Lu X. et al., Mabs.2019 Jan;11(1):45-57.), Asn degradation motifs 110 Attorney Docket No.: 1160430.004613 with relatively higher modification rates may be: NN (Asn-Asn) in CDRH1; NG (Asn-Gly), NH (Asn-His), and NN (Asn-Asn) in CDRH2; NT (Asn-Thr), NF (Asn-Phe), and NY (Asn- Tyr) in CDRH3; NG (Asn-Gly), NH (Asn-His), NS (Asn-Ser), NN (Asn-Asn), and NT (Asn- Thr) in CDRL1; NS (Asn-Ser) and NQ (Asn-Gln) in CDRL2; and NS (Asn-Ser) and NW (Asn-Trp) in CDRL3; and Asp degradation motifs with relatively higher modification rates may be: DD (Asp-Asp) in CDRH1; DG (Asp-Gly) and DD (Asp-Asp) in CDRH2; DG (Asp- Gly), DS (Asp-Ser), DD (Asp-Asp), and DR (Asp-Arg) in CDRH3; DG (Asp-Gly), DS (Asp- Ser), DD (Asp-Asp), DN (Asp-Asn) in CDRL1; DG (Asp-Gly) in CDRL2; and DG (Asp- Gly) and DS (Asp-Ser) in CDRL3.

[0411] Therefore, in some embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi- specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of one or more of these degradation motifs in the above-specified CDR. In certain embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may lack one or more of these degradation motifs in the above-specified CDRs.

[0412] In certain embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of or lack NG in the CDRH2 and / or CDRL1. In certain embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of or lack NH in the CDRL1. In certain embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of or lack NS in the CDRL1. In certain embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of or lack NT in the CDRL1. In certain embodiments, an anti-CD3 antibody or anti- CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of or lack NN in the CDRL1.

[0413] In certain embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of or lack DG in the CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3. In certain embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of or lack DD in the CDRL1. In certain embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced 111 Attorney Docket No.: 1160430.004613 number of or lack DN in the CDRL1. In certain embodiments, an anti-CD3 antibody or anti- CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of or lack DS in the CDRL1.

[0414] In particular embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibody containing an anti-CD3 ABR) according to the disclosure may contain a reduced number of or lack DG, DS, DD, and / or DR in the CDRH3. In particular embodiments, an anti-CD3 antibody or anti-CD3 ABR (multi-specific antibo...

Claims

CLAIMS What is claimed is:

1. A first anti-human cluster of differentiation 3 (CD3) antibody or antigen-binding antibody fragment, which comprises a first heavy chain variable domain (VH-1) comprising: (a) a first heavy chain complementarity determining region (CDR) 1 (CDRH1-1); (b) a first heavy chain CDR2 (CDRH2-1); and (c) a first heavy chain CDR3 (CDRH3-1), wherein: (a) the amino acid sequence of the CDRH1-1 comprises or consists of: a CDR1 amino acid sequence contained in any one of the variable heavy domain of heavy chain (VHH) amino acid sequences listed in Table 13A, 1A, or 24A; and / or any one of the CDR1 amino acid sequences listed in Table 13B, 1B, or 24B; (b) the amino acid sequence of the CDRH2-1 comprises or consists of: a CDR2 amino acid sequence contained in any one of the VHH amino acid sequences listed in Table 13A, 1A, or 24A; and / or any one of the CDR2 amino acid sequences listed in Table 13B, 1B, or 24B; and (c) the amino acid sequence of the CDRH3-1 comprises or consists of: a CDRH3 amino acid sequence contained in any one of the VHH amino acid sequences listed in Table 13A 1A, or 24A; and / or any one of the CDR3 amino acid sequences listed in Table 13B, 1B, or 24B, optionally wherein the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of: (I) (1) (i) SEQ ID NO: 9412, 9414, and 9416, respectively; (ii) SEQ ID NO: 9422, 9424, and 9426, respectively; or (iii) SEQ ID NO: 9432, 9434, and 9436, respectively; (2) (i) SEQ ID NO: 9512, 9514, and 9516, respectively; 380(ii) SEQ ID NO: 9522, 9524, and 9526, respectively; or (iii) SEQ ID NO: 9532, 9534, and 9536, respectively; (3) (i) SEQ ID NO: 9612, 9614, and 9616, respectively; (ii) SEQ ID NO: 9622, 9624, and 9626, respectively; or (iii) SEQ ID NO: 9632, 9634, and 9636, respectively; (4) (i) SEQ ID NO: 9712, 9714, and 9716, respectively; (ii) SEQ ID NO: 9722, 9724, and 9726, respectively; or (iii) SEQ ID NO: 9732, 9734, and 9736, respectively; (5) (i) SEQ ID NO: 9812, 9814, and 9816, respectively; (ii) SEQ ID NO: 9822, 9824, and 9826, respectively; or (iii) SEQ ID NO: 9832, 9834, and 9836, respectively; (6) (i) SEQ ID NO: 9912, 9914, and 9916, respectively; (ii) SEQ ID NO: 9922, 9924, and 9926, respectively; (iii) SEQ ID NO: 9932, 9934, and 9936, respectively; or (iv) SEQ ID NO: 9942, 9944, and 9946, respectively; or (II) (1) SEQ ID NO: 3112, 3114, and 3116, respectively; (2) SEQ ID NO: 3212, 3214, and 3216, respectively; or (3) SEQ ID NO: 3312, 3314, and 3316, respectively, wherein preferably each of the CDRs is that of the same anti-CD3 antibody selected from (1) Antibody Nos.21-h1 through 21-h44, 4-h1 through 4-h34, 14-h1 through 14-h48, 15- h1 through 15-h29, 19-h1 through 19-h32, and 25-h1 through 25-h28, (2) Antibody Nos. 1 through 30, or (3) Antibody Nos.31-48, 22, and 27.

2. The first anti-human CD3 antibody or antigen-binding antibody fragment of claim 1, wherein the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of: 381(a) the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in a VHH amino acid sequence of an anti-CD3 antibody listed in Table 13A, 1A, or 24A; and / or (b) the CDR1, CDR2, and CDR3 amino acid sequences, respectively, of an anti-CD3 antibody listed in Table 13B, 1B, or 24B, optionally wherein said anti-CD3 antibody is: (1) Antibody No.21-h14 or an anti-CD3 antibody selected from (i-1) Antibody No.21- h1; (i-2) Antibody No.21-h2; (i-3) Antibody No.21-h3; (i-4) Antibody No.21-h4; (i- 5) Antibody No.21-h5; (i-6) Antibody No.21-h6; (i-7) Antibody No.21-h7; (i-8) Antibody No.21-h8; (i-9) Antibody No.21-h9; (i-10) Antibody No.21-h10; (i-11) Antibody No.21-h11; (i-12) Antibody No.21-h12; (i-13) Antibody No.21-h13; (i- 14) Antibody No.21-h14; (i-15) Antibody No.21-h15; (i-16) Antibody No.21-h16; (i-17) Antibody No.21-h17; (i-18) Antibody No.21-h18; (i-19) Antibody No.21- h19; (i-20) Antibody No.21-h20; (i-21) Antibody No.21-h21; (i-22) Antibody No. 21-h22; (i-23) Antibody No.21-h23; (i-24) Antibody No.21-h24; (i-25) Antibody No.21-h25; (i-26) Antibody No.21-h26; (i-27) Antibody No.21-h27; (i-28) Antibody No.21-h28; (i-29) Antibody No.21-h29; (i-30) Antibody No.21-h30; (i- 31) Antibody No.21-h31; (i-32) Antibody No.21-h32; (i-33) Antibody No.21-h33; (i-34) Antibody No.21-h34; (i-35) Antibody No.21-h35; (i-36) Antibody No.21- h36; (i-37) Antibody No.21-h37; (i-38) Antibody No.21-h38; (i-39) Antibody No. 21-h39; (i-40) Antibody No.21-h40; (i-41) Antibody No.21-h41; (i-42) Antibody No.21-h42; (i-43) Antibody No.21-h43; or (i-44) Antibody No.21-h44; Antibody No.4-h1, Antibody No.4-h10, or Antibody No.4-h19, or an anti-CD3 antibody selected from (ii-1) Antibody No.4-h1; (ii-2) Antibody No.4-h2; (ii-3) Antibody No.4-h3; (ii-4) Antibody No.4-h4; (ii-5) Antibody No.4-h5; (ii-6) Antibody No.4-h6; (ii-7) Antibody No.4-h7; (ii-8) Antibody No.4-h8; (ii-9) Antibody No.4-h9; (ii-10) Antibody No.4-h10; (ii-11) Antibody No.4-h11; (ii-12) Antibody No.4-h12; (ii-13) Antibody No.4-h13; (ii-14) Antibody No.4-h14; (ii-15) Antibody No.4-h15; (ii-16) Antibody No.4-h16; (ii-17) Antibody No.4-h17; (ii-18) Antibody No.4-h18; (ii-19) Antibody No.4-h19; (ii-20) Antibody No.4-h20; (ii-21) Antibody No.4-h21; (ii-22) Antibody No.4-h22; (ii-23) Antibody No.4-h23; (ii-24) Antibody No.4-h24; (ii-25) Antibody No.4-h25; (ii-26) Antibody No.4-h26; (ii-27) 382Antibody No.4-h27; (ii-28) Antibody No.4-h28; (ii-29) Antibody No.4-h29; (ii-30) Antibody No.4-h30; (ii-31) Antibody No.4-h31; (ii-32) Antibody No.4-h32; (ii-33) Antibody No.4-h33; or (ii-34) Antibody No.4-h34; Antibody No.14-h4, Antibody No.14-h1, Antibody No.14-h19, or Antibody No.14- h27, or an anti-CD3 antibody selected from (iii-1) Antibody No.14-h1; (iii-2) Antibody No.14-h2; (iii-3) Antibody No.14-h3; (iii-4) Antibody No.14-h4; (iii-5) Antibody No.14-h5; (iii-6) Antibody No.14-h6; (iii-7) Antibody No.14-h7; (iii-8) Antibody No.14-h8; (iii-9) Antibody No.14-h9; (iii-10) Antibody No.14-h10; (iii- 11) Antibody No.14-h11; (iii-12) Antibody No.14-h12; (iii-13) Antibody No.14- h13; (iii-14) Antibody No.14-h14; (iii-15) Antibody No.14-h15; (iii-16) Antibody No.14-h16; (iii-17) Antibody No.14-h17; (iii-18) Antibody No.14-h18; (iii-19) Antibody No.14-h19; (iii-20) Antibody No.14-h20; (iii-21) Antibody No.14-h21; (iii-22) Antibody No.14-h22; (iii-23) Antibody No.14-h23; (iii-24) Antibody No.14- h24; (iii-25) Antibody No.14-h25; (iii-26) Antibody No.14-h26; (iii-27) Antibody No.14-h27; (iii-28) Antibody No.14-h28; (iii-29) Antibody No.14-h29; (iii-30) Antibody No.14-h30; (iii-31) Antibody No.14-h31; (iii-32) Antibody No.14-h32; (iii-33) Antibody No.14-h33; (iii-34) Antibody No.14-h34; (iii-35) Antibody No.14- h35; (iii-36) Antibody No.14-h36; (iii-37) Antibody No.14-h37; (iii-38) Antibody No.14-h38; (iii-39) Antibody No.14-h39; (iii-40) Antibody No.14-h40; (iii-41) Antibody No.14-h41; (iii-42) Antibody No.14-h42; (iii-43) Antibody No.14-h43; (iii-44) Antibody No.14-h44; (iii-45) Antibody No.14-h45; (iii-46) Antibody No.14- h46; (iii-47) Antibody No.14-h47; or (iii-48) Antibody No.14-h48; Antibody No.15-h1, Antibody No.15-h6, Antibody No.15-h13, or Antibody No.15- h16, or an anti-CD3 antibody selected from (iv-1) Antibody No.15-h1; (iv-2) Antibody No.15-h2; (iv-3) Antibody No.15-h3; (iv-4) Antibody No.15-h4; (iv-5) Antibody No.15-h5; (iv-6) Antibody No.15-h6; (iv-7) Antibody No.15-h7; (iv-8) Antibody No.15-h8; (iv-9) Antibody No.15-h9; (iv-10) Antibody No.15-h10; (iv- 11) Antibody No.15-h11; (iv-12) Antibody No.15-h12; (iv-13) Antibody No.15- h13; (iv-14) Antibody No.15-h14; (iv-15) Antibody No.15-h15; (iv-16) Antibody No.15-h16; (iv-17) Antibody No.15-h17; (iv-18) Antibody No.15-h18; (iv-19) Antibody No.15-h19; (iv-20) Antibody No.15-h20; (iv-21) Antibody No.15-h21; (iv-22) Antibody No.15-h22; (iv-23) Antibody No.15-h23; (iv-24) Antibody No.15- 383h24; (iv-25) Antibody No.15-h25; (iv-26) Antibody No.15-h26; (iv-27) Antibody No.15-h27; (iv-28) Antibody No.15-h28; or (iv-29) Antibody No.15-h29; Antibody No.19-h3 or Antibody No.19-h29, or an anti-CD3 antibody selected from (v-1) Antibody No.19-h1; (v-2) Antibody No.19-h2; (v-3) Antibody No.19-h3; (v-4) Antibody No.19-h4; (v-5) Antibody No.19-h5; (v-6) Antibody No.19-h6; (v-7) Antibody No.19-h7; (v-8) Antibody No.19-h8; (v-9) Antibody No.19-h9; (v-10) Antibody No.19-h10; (v-11) Antibody No.19-h11; (v-12) Antibody No.19-h12; (v- 13) Antibody No.19-h13; (v-14) Antibody No.19-h14; (v-15) Antibody No.19-h15; (v-16) Antibody No.19-h16; (v-17) Antibody No.19-h17; (v-18) Antibody No.19- h18; (v-19) Antibody No.19-h19; (v-20) Antibody No.19-h20; (v-21) Antibody No. 19-h21; (v-22) Antibody No.19-h22; (v-23) Antibody No.19-h23; (v-24) Antibody No.19-h24; (v-25) Antibody No.19-h25; (v-26) Antibody No.19-h26; (v-27) Antibody No.19-h27; (v-28) Antibody No.19-h28; (v-29) Antibody No.19-h29; (v- 30) Antibody No.19-h30; (v-31) Antibody No.19-h31; or (v-32) Antibody No.19- h32; or Antibody No.25-h3 or Antibody No.25-h12, or an anti-CD3 antibody selected from (vi-1) Antibody No.25-h1; (vi-2) Antibody No.25-h2; (vi-3) Antibody No.25-h3; (vi-4) Antibody No.25-h4; (vi-5) Antibody No.25-h5; (vi-6) Antibody No.25-h6; (vi-7) Antibody No.25-h7; (vi-8) Antibody No.25-h8; (vi-9) Antibody No.25-h9; (vi-10) Antibody No.25-h10; (vi-11) Antibody No.25-h11; (vi-12) Antibody No.25- h12; (vi-13) Antibody No.25-h13; (vi-14) Antibody No.25-h14; (vi-15) Antibody No.25-h15; (vi-16) Antibody No.25-h16; (vi-17) Antibody No.25-h17; (vi-18) Antibody No.25-h18; (vi-19) Antibody No.25-h19; (vi-20) Antibody No.25-h20; (vi-21) Antibody No.25-h21; (vi-22) Antibody No.25-h22; (vi-23) Antibody No.25- h23; (vi-24) Antibody No.25-h24; (vi-25) Antibody No.25-h25; (vi-26) Antibody No.25-h26; (vi-27) Antibody No.25-h27; or (vi-28) Antibody No.25-h28; (2) Antibody No.21, 4, 14, 15, 19, or 25, or an anti-CD3 antibody selected from (i) Antibody No.1; (ii) Antibody No.2; (iii) Antibody No.3; (iv) Antibody No.4; (v) Antibody No.5; (vi) Antibody No.6; (vii) Antibody No.7; (viii) Antibody No.8; (ix) Antibody No.9; (x) Antibody No.10; (xi) Antibody No.11; (xii) Antibody No.12; (xiii) Antibody No.13; (xiv) Antibody No.14; (xv) Antibody No.15; (xvi) Antibody No.16; (xvii) Antibody No.17; (xviii) Antibody No.18; (xix) Antibody No.19; (xx) Antibody No.20; (xxi) Antibody No.21; (xxii) Antibody No.22; (xxiii) Antibody 384No.23; (xxiv) Antibody No.24; (xv) Antibody No.25; (xvi) Antibody No.26; (xvii) Antibody No.27; (xviii) Antibody No.28; (xix) Antibody No.29; or (xxx) Antibody No.30; or (3) (xxxi) Antibody No.31; (xxxii) Antibody No.32; (xxxiii) Antibody No.33; (xxxiv) Antibody No.34; (xxxv) Antibody No.35; (xxxvi) Antibody No.36; (xxxvii) Antibody No.37; (xxxviii) Antibody No.38; (xxxix) Antibody No.39; (xl) Antibody No.40; (xli) Antibody No.41; (xlii) Antibody No.42; (xliii) Antibody No.43; (xliv) Antibody No.44; (xlv) Antibody No.45; (xlvi) Antibody No.46; (xlvii) Antibody No.47; or (xlviii) Antibody No.

48.

3. The first anti-human CD3 antibody or antigen-binding antibody fragment of claim 1 or 2, wherein the amino acid sequence of the VH-1 comprises or consists of: (a) the VHH amino acid sequence of the anti-CD3 antibody listed in Table 13A, 1A, or 24A; or (b) a variant thereof having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to said VHH amino acid sequence.

4. The first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-3, wherein the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of: (a) the CDR1, CDR2, and CDR3 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (1) SEQ ID NO: 4140 or any of (i-1) SEQ ID NO: 4010; (i-2) SEQ ID NO: 4020; (i- 3) SEQ ID NO: 4030; (i-4) SEQ ID NO: 4040; (i-5) SEQ ID NO: 4050; (i-6) SEQ ID NO: 4060; (i-7) SEQ ID NO: 4070; (i-8) SEQ ID NO: 4080; (i-9) SEQ ID NO: 4090; (i-10) SEQ ID NO: 4100; (i-11) SEQ ID NO: 4110; (i-12) SEQ ID NO: 4120; (i-13) SEQ ID NO: 4130; (i-14) SEQ ID NO: 4140; (i-15) SEQ ID NO: 4150; (i-16) SEQ ID NO: 4160; (i-17) SEQ ID NO: 4170; (i-18) SEQ ID NO: 4180; (i-19) SEQ ID NO: 4190; (i-20) SEQ ID NO: 4200; (i-21) SEQ ID NO: 4210; (i-22) SEQ ID NO: 4220; (i-23) SEQ ID NO: 4230; (i-24) SEQ ID NO: 4240; (i-25) SEQ ID NO: 4250; (i-26) SEQ ID NO: 4260; (i-27) SEQ ID NO: 3854270; (i-28) SEQ ID NO: 4280; (i-29) SEQ ID NO: 4290; (i-30) SEQ ID NO: 4300; (i-31) SEQ ID NO: 4310; (i-32) SEQ ID NO: 4320; (i-33) SEQ ID NO: 4330; (i-34) SEQ ID NO: 4340; (i-35) SEQ ID NO: 4350; (i-36) SEQ ID NO: 4360; (i-37) SEQ ID NO: 4370; (i-38) SEQ ID NO: 4380; (i-39) SEQ ID NO: 4390; (i-40) SEQ ID NO: 4400; (i-41) SEQ ID NO: 4410; (i-42) SEQ ID NO: 4420; (i-43) SEQ ID NO: 4430; or (i-44) SEQ ID NO: 4440; SEQ ID NO: 5010, 5100, or 5190, or any of (ii-1) SEQ ID NO: 5010; (ii-2) SEQ ID NO: 5020; (ii-3) SEQ ID NO: 5030; (ii-4) SEQ ID NO: 5040; (ii-5) SEQ ID NO: 5050; (ii-6) SEQ ID NO: 5060; (ii-7) SEQ ID NO: 5070; (ii-8) SEQ ID NO: 5080; (ii-9) SEQ ID NO: 5090; (ii-10) SEQ ID NO: 5100; (ii-11) SEQ ID NO: 5110; (ii-12) SEQ ID NO: 5120; (ii-13) SEQ ID NO: 5130; (ii-14) SEQ ID NO: 5140; (ii-15) SEQ ID NO: 5150; (ii-16) SEQ ID NO: 5160; (ii-17) SEQ ID NO: 5170; (ii-18) SEQ ID NO: 5180; (ii-19) SEQ ID NO: 5190; (ii-20) SEQ ID NO: 5200; (ii-21) SEQ ID NO: 5210; (ii-22) SEQ ID NO: 5220; (ii-23) SEQ ID NO: 5230; (ii-24) SEQ ID NO: 5240; (ii-25) SEQ ID NO: 5250; (ii-26) SEQ ID NO: 5260; (ii-27) SEQ ID NO: 5270; (ii-28) SEQ ID NO: 5280; (ii-29) SEQ ID NO: 5290; (ii-30) SEQ ID NO: 5300; (ii-31) SEQ ID NO: 5310; (ii-32) SEQ ID NO: 5320; (ii-33) SEQ ID NO: 5330; or (ii-34) SEQ ID NO: 5340; SEQ ID NO: 6040, 6010, 6190, or 6270, or any of (iii-1) SEQ ID NO: 6010; (iii- 2) SEQ ID NO: 6020; (iii-3) SEQ ID NO: 6030; (iii-4) SEQ ID NO: 6040; (iii-5) SEQ ID NO: 6050; (iii-6) SEQ ID NO: 6060; (iii-7) SEQ ID NO: 6070; (iii-8) SEQ ID NO: 6080; (iii-9) SEQ ID NO: 6090; (iii-10) SEQ ID NO: 6100; (iii-11) SEQ ID NO: 6110; (iii-12) SEQ ID NO: 6120; (iii-13) SEQ ID NO: 6130; (iii-14) SEQ ID NO: 6140; (iii-15) SEQ ID NO: 6150; (iii-16) SEQ ID NO: 6160; (iii-17) SEQ ID NO: 6170; (iii-18) SEQ ID NO: 6180; (iii-19) SEQ ID NO: 6190; (iii-20) SEQ ID NO: 6200; (iii-21) SEQ ID NO: 6210; (iii-22) SEQ ID NO: 6220; (iii-23) SEQ ID NO: 6230; (iii-24) SEQ ID NO: 6240; (iii-25) SEQ ID NO: 6250; (iii-26) SEQ ID NO: 6260; (iii-27) SEQ ID NO: 6270; (iii-28) SEQ ID NO: 6280; (iii-29) SEQ ID NO: 6290; (iii-30) SEQ ID NO: 6300; (iii-31) SEQ ID NO: 6310; (iii-32) SEQ ID NO: 6320; (iii-33) SEQ ID NO: 6330; (iii-34) SEQ ID NO: 6340; (iii-35) SEQ ID NO: 6350; (iii-36) SEQ ID NO: 6360; (iii-37) SEQ ID NO: 6370; (iii-38) SEQ ID NO: 6380; (iii-39) SEQ ID NO: 6390; (iii-40) SEQ ID NO: 6400; (iii-41) SEQ ID NO: 6410; (iii-42) SEQ ID NO: 6420; (iii-43) SEQ ID NO: 6430; (iii-44) 386SEQ ID NO: 6440; (iii-45) SEQ ID NO: 6450; (iii-46) SEQ ID NO: 6460; (iii-47) SEQ ID NO: 6470; or (iii-48) SEQ ID NO: 6480; SEQ ID NO: 7010, 7060, 7130, or 7160, or any of (iv-1) SEQ ID NO: 7010; (iv-2) SEQ ID NO: 7020; (iv-3) SEQ ID NO: 7030; (iv-4) SEQ ID NO: 7040; (iv-5) SEQ ID NO: 7050; (iv-6) SEQ ID NO: 7060; (iv-7) SEQ ID NO: 7070; (iv-8) SEQ ID NO: 7080; (iv-9) SEQ ID NO: 7090; (iv-10) SEQ ID NO: 7100; (iv-11) SEQ ID NO: 7110; (iv-12) SEQ ID NO: 7120; (iv-13) SEQ ID NO: 7130; (iv-14) SEQ ID NO: 7140; (iv-15) SEQ ID NO: 7150; (iv-16) SEQ ID NO: 7160; (iv-17) SEQ ID NO: 7170; (iv-18) SEQ ID NO: 7180; (iv-19) SEQ ID NO: 7190; (iv-20) SEQ ID NO: 7200; (iv-21) SEQ ID NO: 7210; (iv-22) SEQ ID NO: 7220; (iv-23) SEQ ID NO: 7230; (iv-24) SEQ ID NO: 7240; (iv-25) SEQ ID NO: 7250; (iv-26) SEQ ID NO: 7260; (iv-27) SEQ ID NO: 7270; (iv-28) SEQ ID NO: 7280; or (iv- 29) SEQ ID NO: 7290; SEQ ID NO: 8030 or 8290, or any of (v-1) SEQ ID NO: 8010; (v-2) SEQ ID NO: 8020; (v-3) SEQ ID NO: 8030; (v-4) SEQ ID NO: 8040; (v-5) SEQ ID NO: 8050; (v-6) SEQ ID NO: 8060; (v-7) SEQ ID NO: 8070; (v-8) SEQ ID NO: 8080; (v-9) SEQ ID NO: 8090; (v-10) SEQ ID NO: 8100; (v-11) SEQ ID NO: 8110; (v-12) SEQ ID NO: 8120; (v-13) SEQ ID NO: 8130; (v-14) SEQ ID NO: 8140; (v-15) SEQ ID NO: 8150; (v-16) SEQ ID NO: 8160; (v-17) SEQ ID NO: 8170; (v-18) SEQ ID NO: 8180; (v-19) SEQ ID NO: 8190; (v-20) SEQ ID NO: 8200; (v-21) SEQ ID NO: 8210; (v-22) SEQ ID NO: 8220; (v-23) SEQ ID NO: 8230; (v-24) SEQ ID NO: 8240; (v-25) SEQ ID NO: 8250; (v-26) SEQ ID NO: 8260; (v-27) SEQ ID NO: 8270; (v-28) SEQ ID NO: 8280; (v-29) SEQ ID NO: 8290; (v-30) SEQ ID NO: 8300; (v-31) SEQ ID NO: 8310; or (v-32) SEQ ID NO: 8320; or SEQ ID NO: 9030 or 9120, or any of (vi-1) SEQ ID NO: 9010; (vi-2) SEQ ID NO: 9020; (vi-3) SEQ ID NO: 9030; (vi-4) SEQ ID NO: 9040; (vi-5) SEQ ID NO: 9050; (vi-6) SEQ ID NO: 9060; (vi-7) SEQ ID NO: 9070; (vi-8) SEQ ID NO: 9080; (vi-9) SEQ ID NO: 9090; (vi-10) SEQ ID NO: 9100; (vi-11) SEQ ID NO: 9110; (vi-12) SEQ ID NO: 9120; (vi-13) SEQ ID NO: 9130; (vi-14) SEQ ID NO: 9140; (vi-15) SEQ ID NO: 9150; (vi-16) SEQ ID NO: 9160; (vi-17) SEQ ID NO: 9170; (vi-18) SEQ ID NO: 9180; (vi-19) SEQ ID NO: 9190; (vi-20) SEQ ID NO: 9200; (vi-21) SEQ ID NO: 9210; (vi-22) SEQ ID NO: 9220; (vi-23) SEQ ID 387NO: 9230; (vi-24) SEQ ID NO: 9240; (vi-25) SEQ ID NO: 9250; (vi-26) SEQ ID NO: 9260; (vi-27) SEQ ID NO: 9270; or (vi-28) SEQ ID NO: 9280; (2) (i) SEQ ID NOS: 110; (ii) SEQ ID NO: 210; (iii) SEQ ID NO: 310; (iv) SEQ ID NO: 410; (v) SEQ ID NO: 510; (vi) SEQ ID NO: 610; (vii) SEQ ID NO: 710; (viii) SEQ ID NO: 810; (ix) SEQ ID NO: 910; (x) SEQ ID NO: 1010; (xi) SEQ ID NO: 1110; (xii) SEQ ID NO: 1210; (xiii) SEQ ID NO: 1310; (xiv) SEQ ID NO: 1410; (xv) SEQ ID NO: 1510; (xvi) SEQ ID NO: 1610; (xvii) SEQ ID NO: 1710; (xviii) SEQ ID NO: 1810; (xix) SEQ ID NO: 1910; (xx) SEQ ID NO: 2010; (xxi) SEQ ID NO: 2110; (xxii) SEQ ID NO: 2210; (xxiii) SEQ ID NO: 2310; (xxiv) SEQ ID NO: 2410; (xxv) SEQ ID NO: 2510; (xxvi) SEQ ID NO: 2610; (xxvii) SEQ ID NO: 2710; (xxviii) SEQ ID NO: 2810; (xxix) SEQ ID NO: 2910; or (xxx) SEQ ID NO: 3010; and / or (3) (xxxi) SEQ ID NOS: 10110; (xxxii) SEQ ID NO: 10210; (xxxiii) SEQ ID NO: 10310; (xxxiv) SEQ ID NO: 10410; (xxxv) SEQ ID NO: 10510; (xxxvi) SEQ ID NO: 10610; (xxxvii) SEQ ID NO: 10710; (xxxviii) SEQ ID NO: 10810; (xxxix) SEQ ID NO: 10910; (xl) SEQ ID NO: 11010; (xli) SEQ ID NO: 11110; (xlii) SEQ ID NO: 11210; (xliii) SEQ ID NO: 11310; (xliv) SEQ ID NO: 11410; (xlv) SEQ ID NO: 11510; (xlvi) SEQ ID NO: 11610; (xlvii) SEQ ID NO: 11710; or (xlviii) SEQ ID NO: 11810; (b) the CDR1, CDR2, and CDR3 amino acid sequences of: (1) SEQ ID NOS: 4142, 4144, and 4146, respectively, or any of (i-1) SEQ ID NOS: 4012, 4014, and 4016, respectively; (i-2) SEQ ID NOS: 4022, 4024, and 4026, respectively; (i-3) SEQ ID NOS: 4032, 4034, and 4036, respectively; (i-4) SEQ ID NOS: 4042, 4044, and 4046, respectively; (i-5) SEQ ID NOS: 4052, 4054, and 4056, respectively; (i-6) SEQ ID NOS: 4062, 4064, and 4066, respectively; (i-7) SEQ ID NOS: 4072, 4074, and 4076, respectively; (i-8) SEQ ID NOS: 4082, 4084, and 4086, respectively; (i-9) SEQ ID NOS: 4092, 4094, and 4096, respectively; (i-10) SEQ ID NOS: 4102, 4104, and 4106, respectively; (i-11) SEQ ID NOS: 4112, 4114, and 4116, respectively; (i-12) SEQ ID NOS: 4122, 4124, and 4126, respectively; (i-13) SEQ ID NOS: 4132, 4134, and 4136, respectively; (i-14) SEQ ID NOS: 4142, 4144, and 4146, respectively; (i-15) SEQ ID NOS: 4152, 4154, and 4156, respectively; (i-16) SEQ ID NOS: 4162, 4164, and 4166, 388respectively; (i-17) SEQ ID NOS: 4172, 4174, and 4176, respectively; (i-18) SEQ ID NOS: 4182, 4184, and 4186, respectively; (i-19) SEQ ID NOS: 4192, 4194, and 4196, respectively; (i-20) SEQ ID NOS: 4202, 4204, and 4206, respectively; (i-21) SEQ ID NOS: 4212, 4214, and 4216, respectively; (i-22) SEQ ID NOS: 4222, 4224, and 4226, respectively; (i-23) SEQ ID NOS: 4232, 4234, and 4236, respectively; (i-24) SEQ ID NOS: 4242, 4244, and 4246, respectively; (i-25) SEQ ID NOS: 4252, 4254, and 4256, respectively; (i-26) SEQ ID NOS: 4262, 4264, and 4266, respectively; (i-27) SEQ ID NOS: 4272, 4274, and 4276, respectively; (i-28) SEQ ID NOS: 4282, 4284, and 4286, respectively; (i-29) SEQ ID NOS: 4292, 4294, and 4296, respectively; (i-30) SEQ ID NOS: 4302, 4304, and 4306, respectively; (i-31) SEQ ID NOS: 4312, 4314, and 4316, respectively; (i-32) SEQ ID NOS: 4322, 4324, and 4326, respectively; (i-33) SEQ ID NOS: 4332, 4334, and 4336, respectively; (i-34) SEQ ID NOS: 4342, 4344, and 4346, respectively; (i-35) SEQ ID NOS: 4352, 4354, and 4356, respectively; (i-36) SEQ ID NOS: 4362, 4364, and 4366, respectively; (i-37) SEQ ID NOS: 4372, 4374, and 4376, respectively; (i-38) SEQ ID NOS: 4382, 4384, and 4386, respectively; (i-39) SEQ ID NOS: 4392, 4394, and 4396, respectively; (i-40) SEQ ID NOS: 4402, 4404, and 4406, respectively; (i-41) SEQ ID NOS: 4412, 4414, and 4416, respectively; (i-42) SEQ ID NOS: 4422, 4424, and 4426, respectively; (i-43) SEQ ID NOS: 4432, 4434, and 4436, respectively; or (i-44) SEQ ID NOS: 4442, 4444, and 4446, respectively; SEQ ID NOS: 5012, 5014, and 5016, respectively, SEQ ID NOS: 5102, 5104, and 5106, respectively, or SEQ ID NOS: 5192, 5194, and 5196, respectively, or any of (ii-1) SEQ ID NOS: 5012, 5014, and 5016, respectively; (ii-2) SEQ ID NOS: 5022, 5024, and 5026, respectively; (ii-3) SEQ ID NOS: 5032, 5034, and 5036, respectively; (ii-4) SEQ ID NOS: 5042, 5044, and 5046, respectively; (ii-5) SEQ ID NOS: 5052, 5054, and 5056, respectively; (ii-6) SEQ ID NOS: 5062, 5064, and 5066, respectively; (ii-7) SEQ ID NOS: 5072, 5074, and 5076, respectively; (ii-8) SEQ ID NOS: 5082, 5084, and 5086, respectively; (ii-9) SEQ ID NOS: 5092, 5094, and 5096, respectively; (ii-10) SEQ ID NOS: 5102, 5104, and 5106, respectively; (ii-11) SEQ ID NOS: 5112, 5114, and 5116, respectively; (ii-12) SEQ ID NOS: 5122, 5124, and 5126, respectively; (ii-13) SEQ ID NOS: 5132, 5134, and 5136, respectively; (ii-14) SEQ ID NOS: 5142, 5144, and 5146, 389respectively; (ii-15) SEQ ID NOS: 5152, 5154, and 5156, respectively; (ii-16) SEQ ID NOS: 5162, 5164, and 5166, respectively; (ii-17) SEQ ID NOS: 5172, 5174, and 5176, respectively; (ii-18) SEQ ID NOS: 5182, 5184, and 5186, respectively; (ii-19) SEQ ID NOS: 5192, 5194, and 5196, respectively; (ii-20) SEQ ID NOS: 5202, 5204, and 5206, respectively; (ii-21) SEQ ID NOS: 5212, 5214, and 5216, respectively; (ii-22) SEQ ID NOS: 5222, 5224, and 5226, respectively; (ii-23) SEQ ID NOS: 5232, 5234, and 5236, respectively; (ii-24) SEQ ID NOS: 5242, 5244, and 5246, respectively; (ii-25) SEQ ID NOS: 5252, 5254, and 5256, respectively; (ii-26) SEQ ID NOS: 5262, 5264, and 5266, respectively; (ii-27) SEQ ID NOS: 5272, 5274, and 5276, respectively; (ii-28) SEQ ID NOS: 5282, 5284, and 5286, respectively; (ii-29) SEQ ID NOS: 5292, 5294, and 5296, respectively; (ii-30) SEQ ID NOS: 5302, 5304, and 5306, respectively; (ii-31) SEQ ID NOS: 5312, 5314, and 5316, respectively; (ii-32) SEQ ID NOS: 5322, 5324, and 5326, respectively; (ii-33) SEQ ID NOS: 5332, 5334, and 5336, respectively; or (ii-34) SEQ ID NOS: 5342, 5344, and 5346, respectively; SEQ ID NOS: 6042, 6044, and 6046, respectively, SEQ ID NOS: 6012, 6014, and 6016, respectively, SEQ ID NOS: 6192, 6194, and 6196, respectively, or SEQ ID NOS: 6272, 6274, and 6276, respectively, or any of (iii-1) SEQ ID NOS: 6012, 6014, and 6016, respectively; (iii-2) SEQ ID NOS: 6022, 6024, and 6026, respectively; (iii-3) SEQ ID NOS: 6032, 6034, and 6036, respectively; (iii-4) SEQ ID NOS: 6042, 6044, and 6046, respectively; (iii-5) SEQ ID NOS: 6052, 6054, and 6056, respectively; (iii-6) SEQ ID NOS: 6062, 6064, and 6066, respectively; (iii-7) SEQ ID NOS: 6072, 6074, and 6076, respectively; (iii-8) SEQ ID NOS: 6082, 6084, and 6086, respectively; (iii-9) SEQ ID NOS: 6092, 6094, and 6096, respectively; (iii-10) SEQ ID NOS: 6102, 6104, and 6106, respectively; (iii-11) SEQ ID NOS: 6112, 6114, and 6116, respectively; (iii-12) SEQ ID NOS: 6122, 6124, and 6126, respectively; (iii-13) SEQ ID NOS: 6132, 6134, and 6136, respectively; (iii-14) SEQ ID NOS: 6142, 6144, and 6146, respectively; (iii-15) SEQ ID NOS: 6152, 6154, and 6156, respectively; (iii-16) SEQ ID NOS: 6162, 6164, and 6166, respectively; (iii-17) SEQ ID NOS: 6172, 6174, and 6176, respectively; (iii-18) SEQ ID NOS: 6182, 6184, and 6186, respectively; (iii-19) SEQ ID NOS: 6192, 6194, and 6196, respectively; (iii-20) SEQ ID NOS: 6202, 3906204, and 6206, respectively; (iii-21) SEQ ID NOS: 6212, 6214, and 6216, respectively; (iii-22) SEQ ID NOS: 6222, 6224, and 6226, respectively; (iii-23) SEQ ID NOS: 6232, 6234, and 6236, respectively; (iii-24) SEQ ID NOS: 6242, 6244, and 6246, respectively; (iii-25) SEQ ID NOS: 6252, 6254, and 6256, respectively; (iii-26) SEQ ID NOS: 6262, 6264, and 6266, respectively; (iii-27) SEQ ID NOS: 6272, 6274, and 6276, respectively; (iii-28) SEQ ID NOS: 6282, 6284, and 6286, respectively; (iii-29) SEQ ID NOS: 6292, 6294, and 6296, respectively; (iii-30) SEQ ID NOS: 6302, 6304, and 6306, respectively; (iii-31) SEQ ID NOS: 6312, 6314, and 6316, respectively; (iii-32) SEQ ID NOS: 6322, 6324, and 6326, respectively; (iii-33) SEQ ID NOS: 6332, 6334, and 6336, respectively; (iii-34) SEQ ID NOS: 6342, 6344, and 6346, respectively; (iii-35) SEQ ID NOS: 6352, 6354, and 6356, respectively; (iii-36) SEQ ID NOS: 6362, 6364, and 6366, respectively; (iii-37) SEQ ID NOS: 6372, 6374, and 6376, respectively; (iii-38) SEQ ID NOS: 6382, 6384, and 6386, respectively; (iii-39) SEQ ID NOS: 6392, 6394, and 6396, respectively; (iii-40) SEQ ID NOS: 6402, 6404, and 6406, respectively; (iii-41) SEQ ID NOS: 6412, 6414, and 6416, respectively; (iii-42) SEQ ID NOS: 6422, 6424, and 6426, respectively; (iii-43) SEQ ID NOS: 6432, 6434, and 6436, respectively; (iii-44) SEQ ID NOS: 6442, 6444, and 6446, respectively; (iii-45) SEQ ID NOS: 6452, 6454, and 6456, respectively; (iii-46) SEQ ID NOS: 6462, 6464, and 6466, respectively; (iii-47) SEQ ID NOS: 6472, 6474, and 6476, respectively; or (iii-48) SEQ ID NOS: 6482, 6484, and 6486, respectively; SEQ ID NOS: 7012, 7014, and 7016, respectively, SEQ ID NOS: 7062, 7064, and 7066, respectively, SEQ ID NOS: 7132, 7134, and 7136, respectively, or SEQ ID NOS: 7162, 7164, and 7166, respectively, or any of (iv-1) SEQ ID NOS: 7012, 7014, and 7016, respectively; (iv-2) SEQ ID NOS: 7022, 7024, and 7026, respectively; (iv-3) SEQ ID NOS: 7032, 7034, and 7036, respectively; (iv-4) SEQ ID NOS: 7042, 7044, and 7046, respectively; (iv-5) SEQ ID NOS: 7052, 7054, and 7056, respectively; (iv-6) SEQ ID NOS: 7062, 7064, and 7066, respectively; (iv-7) SEQ ID NOS: 7072, 7074, and 7076, respectively; (iv-8) SEQ ID NOS: 7082, 7084, and 7086, respectively; (iv-9) SEQ ID NOS: 7092, 7094, and 7096, respectively; (iv-10) SEQ ID NOS: 7102, 7104, and 7106, respectively; (iv-11) SEQ ID NOS: 7112, 7114, and 7116, respectively; (iv-12) SEQ ID NOS: 7122, 3917124, and 7126, respectively; (iv-13) SEQ ID NOS: 7132, 7134, and 7136, respectively; (iv-14) SEQ ID NOS: 7142, 7144, and 7146, respectively; (iv-15) SEQ ID NOS: 7152, 7154, and 7156, respectively; (iv-16) SEQ ID NOS: 7162, 7164, and 7166, respectively; (iv-17) SEQ ID NOS: 7172, 7174, and 7176, respectively; (iv-18) SEQ ID NOS: 7182, 7184, and 7186, respectively; (iv-19) SEQ ID NOS: 7192, 7194, and 7196, respectively; (iv-20) SEQ ID NOS: 7202, 7204, and 7206, respectively; (iv-21) SEQ ID NOS: 7212, 7214, and 7216, respectively; (iv-22) SEQ ID NOS: 7222, 7224, and 7226, respectively; (iv-23) SEQ ID NOS: 7232, 7234, and 7236, respectively; (iv-24) SEQ ID NOS: 7242, 7244, and 7246, respectively; (iv-25) SEQ ID NOS: 7252, 7254, and 7256, respectively; (iv-26) SEQ ID NOS: 7262, 7264, and 7266, respectively; (iv-27) SEQ ID NOS: 7272, 7274, and 7276, respectively; (iv-28) SEQ ID NOS: 7282, 7284, and 7286, respectively; or (iv-29) SEQ ID NOS: 7292, 7294, and 7296, respectively; SEQ ID NOS: 8032, 8034, and 8036, respectively, or SEQ ID NOS: 8292, 8294, and 8296, respectively, or any of (v-1) SEQ ID NOS: 8012, 8014, and 8016, respectively; (v-2) SEQ ID NOS: 8022, 8024, and 8026, respectively; (v-3) SEQ ID NOS: 8032, 8034, and 8036, respectively; (v-4) SEQ ID NOS: 8042, 8044, and 8046, respectively; (v-5) SEQ ID NOS: 8052, 8054, and 8056, respectively; (v-6) SEQ ID NOS: 8062, 8064, and 8066, respectively; (v-7) SEQ ID NOS: 8072, 8074, and 8076, respectively; (v-8) SEQ ID NOS: 8082, 8084, and 8086, respectively; (v-9) SEQ ID NOS: 8092, 8094, and 8096, respectively; (v-10) SEQ ID NOS: 8102, 8104, and 8106, respectively; (v-11) SEQ ID NOS: 8112, 8114, and 8116, respectively; (v-12) SEQ ID NOS: 8122, 8124, and 8126, respectively; (v-13) SEQ ID NOS: 8132, 8134, and 8136, respectively; (v-14) SEQ ID NOS: 8142, 8144, and 8146, respectively; (v-15) SEQ ID NOS: 8152, 8154, and 8156, respectively; (v-16) SEQ ID NOS: 8162, 8164, and 8166, respectively; (v-17) SEQ ID NOS: 8172, 8174, and 8176, respectively; (v-18) SEQ ID NOS: 8182, 8184, and 8186, respectively; (v-19) SEQ ID NOS: 8192, 8194, and 8196, respectively; (v-20) SEQ ID NOS: 8202, 8204, and 8206, respectively; (v-21) SEQ ID NOS: 8212, 8214, and 8216, respectively; (v-22) SEQ ID NOS: 8222, 8224, and 8226, respectively; (v-23) SEQ ID NOS: 8232, 8234, and 8236, respectively; (v-24) SEQ ID NOS: 8242, 8244, and 8246, respectively; (v-25) 392SEQ ID NOS: 8252, 8254, and 8256, respectively; (v-26) SEQ ID NOS: 8262, 8264, and 8266, respectively; (v-27) SEQ ID NOS: 8272, 8274, and 8276, respectively; (v-28) SEQ ID NOS: 8282, 8284, and 8286, respectively; (v-29) SEQ ID NOS: 8292, 8294, and 8296, respectively; (v-30) SEQ ID NOS: 8302, 8304, and 8306, respectively; (v-31) SEQ ID NOS: 8312, 8314, and 8316, respectively; or (v-32) SEQ ID NOS: 8322, 8324, and 8326, respectively; or SEQ ID NOS: 9032, 9034, and 9036, respectively, or SEQ ID NOS: 9122, 9124, and 9126, respectively, or any of (vi-1) SEQ ID NOS: 9012, 9014, and 9016, respectively; (vi-2) SEQ ID NOS: 9022, 9024, and 9026, respectively; (vi-3) SEQ ID NOS: 9032, 9034, and 9036, respectively; (vi-4) SEQ ID NOS: 9042, 9044, and 9046, respectively; (vi-5) SEQ ID NOS: 9052, 9054, and 9056, respectively; (vi-6) SEQ ID NOS: 9062, 9064, and 9066, respectively; (vi-7) SEQ ID NOS: 9072, 9074, and 9076, respectively; (vi-8) SEQ ID NOS: 9082, 9084, and 9086, respectively; (vi-9) SEQ ID NOS: 9092, 9094, and 9096, respectively; (vi-10) SEQ ID NOS: 9102, 9104, and 9106, respectively; (vi-11) SEQ ID NOS: 9112, 9114, and 9116, respectively; (vi-12) SEQ ID NOS: 9122, 9124, and 9126, respectively; (vi-13) SEQ ID NOS: 9132, 9134, and 9136, respectively; (vi-14) SEQ ID NOS: 9142, 9144, and 9146, respectively; (vi-15) SEQ ID NOS: 9152, 9154, and 9156, respectively; (vi-16) SEQ ID NOS: 9162, 9164, and 9166, respectively; (vi-17) SEQ ID NOS: 9172, 9174, and 9176, respectively; (vi-18) SEQ ID NOS: 9182, 9184, and 9186, respectively; (vi-19) SEQ ID NOS: 9192, 9194, and 9196, respectively; (vi-20) SEQ ID NOS: 9202, 9204, and 9206, respectively; (vi-21) SEQ ID NOS: 9212, 9214, and 9216, respectively; (vi-22) SEQ ID NOS: 9222, 9224, and 9226, respectively; (vi-23) SEQ ID NOS: 9232, 9234, and 9236, respectively; (vi-24) SEQ ID NOS: 9242, 9244, and 9246, respectively; (vi-25) SEQ ID NOS: 9252, 9254, and 9256, respectively; (vi-26) SEQ ID NOS: 9262, 9264, and 9266, respectively; (vi-27) SEQ ID NOS: 9272, 9274, and 9276, respectively; or (vi-28) SEQ ID NOS: 9282, 9284, and 9286, respectively; (2) (i) SEQ ID NOS: 112, 114, and 116, respectively; (ii) SEQ ID NOS: 212, 214, and 216, respectively; (iii) SEQ ID NOS: 312, 314, and 316, respectively; (iv) SEQ ID NOS: 412, 414, and 416, respectively; (v) SEQ ID NOS: 512, 514, and 516, respectively; (vi) SEQ ID NOS: 612, 614, and 616, respectively; (vii) SEQ ID 393NOS: 712, 714, and 716, respectively; (viii) SEQ ID NOS: 812, 814, and 816, respectively; (ix) SEQ ID NOS: 912, 914, and 916, respectively; (x) SEQ ID NOS: 1012, 1014, and 1016, respectively; (xi) SEQ ID NOS: 1112, 1114, and 1116, respectively; (xii) SEQ ID NOS: 1212, 1214, and 1216, respectively; (xiii) SEQ ID NOS: 1312, 1314, and 1316, respectively; (xiv) SEQ ID NOS: 1412, 1414, and 1416, respectively; (xv) SEQ ID NOS: 1512, 1514, and 1516, respectively; (xvi) SEQ ID NOS: 1612, 1614, and 1616, respectively; (xvii) SEQ ID NOS: 1712, 1714, and 1716, respectively; (xviii) SEQ ID NOS: 1812, 1814, and 1816, respectively; (xix) SEQ ID NOS: 1912, 1914, and 1916, respectively; (xx) SEQ ID NOS: 2012, 2014, and 2016, respectively; (xxi) SEQ ID NOS: 2112, 2114, and 2116, respectively; (xxii) SEQ ID NOS: 2212, 2214, and 2216, respectively; (xxiii) SEQ ID NOS: 2312, 2314, and 2316, respectively; (xxiv) SEQ ID NOS: 2412, 2414, and 2416, respectively; (xxv) SEQ ID NOS: 2512, 2514, and 2516, respectively; (xxvi) SEQ ID NOS: 2612, 2614, and 2616, respectively; (xxvii) SEQ ID NOS: 2712, 2714, and 2716, respectively; (xxviii) SEQ ID NOS: 2812, 2814, and 2816, respectively; (xxix) SEQ ID NOS: 2912, 2914, and 2916, respectively; or (xxx) SEQ ID NOS: 3012, 3014, and 3016, respectively; and / or (3) (xxxi) SEQ ID NOS: 10112, 10114, and 10116, respectively; (xxxii) SEQ ID NOS: 10212, 10214, and 10216, respectively; (xxxiii) SEQ ID NOS: 10312, 10314, and 10316, respectively; (xxxiv) SEQ ID NOS: 10412, 10414, and 10416, respectively; (xxxv) SEQ ID NOS: 10512, 10514, and 10516, respectively; (xxxvi) SEQ ID NOS: 10612, 10614, and 10616, respectively; (xxxvii) SEQ ID NOS: 10712, 10714, and 10716, respectively; (xxxviii) SEQ ID NOS: 10812, 10814, and 10816, respectively; (xxxix) SEQ ID NOS: 10912, 10914, and 10916, respectively; (xl) SEQ ID NOS: 11012, 11014, and 11016, respectively; (xli) SEQ ID NOS: 11112, 11114, and 11116, respectively; (xlii) SEQ ID NOS: 11212, 11214, and 11216, respectively; (xliii) SEQ ID NOS: 11312, 11314, and 11316, respectively; (xliv) SEQ ID NOS: 11412, 11414, and 11416, respectively; (xlv) SEQ ID NOS: 11512, 11514, and 11516, respectively; (xlvi) SEQ ID NOS: 11612, 11614, and 11616, respectively; (xlvii) SEQ ID NOS: 11712, 11714, and 11716, respectively; or (xlviii) SEQ ID NOS: 11812, 11814, and 11816, respectively. 3945. The first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-4, wherein: the amino acid sequence of the VH-1 comprises or consists of: (a) the VHH amino acid sequence of: (1) SEQ ID NO: 4140 or any of (i-1) SEQ ID NO: 4010; (i-2) SEQ ID NO: 4020; (i- 3) SEQ ID NO: 4030; (i-4) SEQ ID NO: 4040; (i-5) SEQ ID NO: 4050; (i-6) SEQ ID NO: 4060; (i-7) SEQ ID NO: 4070; (i-8) SEQ ID NO: 4080; (i-9) SEQ ID NO: 4090; (i-10) SEQ ID NO: 4100; (i-11) SEQ ID NO: 4110; (i-12) SEQ ID NO: 4120; (i-13) SEQ ID NO: 4130; (i-14) SEQ ID NO: 4140; (i-15) SEQ ID NO: 4150; (i-16) SEQ ID NO: 4160; (i-17) SEQ ID NO: 4170; (i-18) SEQ ID NO: 4180; (i-19) SEQ ID NO: 4190; (i-20) SEQ ID NO: 4200; (i-21) SEQ ID NO: 4210; (i-22) SEQ ID NO: 4220; (i-23) SEQ ID NO: 4230; (i-24) SEQ ID NO: 4240; (i-25) SEQ ID NO: 4250; (i-26) SEQ ID NO: 4260; (i-27) SEQ ID NO: 4270; (i-28) SEQ ID NO: 4280; (i-29) SEQ ID NO: 4290; (i-30) SEQ ID NO: 4300; (i-31) SEQ ID NO: 4310; (i-32) SEQ ID NO: 4320; (i-33) SEQ ID NO: 4330; (i-34) SEQ ID NO: 4340; (i-35) SEQ ID NO: 4350; (i-36) SEQ ID NO: 4360; (i-37) SEQ ID NO: 4370; (i-38) SEQ ID NO: 4380; (i-39) SEQ ID NO: 4390; (i-40) SEQ ID NO: 4400; (i-41) SEQ ID NO: 4410; (i-42) SEQ ID NO: 4420; (i-43) SEQ ID NO: 4430; or (i-44) SEQ ID NO: 4440; SEQ ID NO: 5010, 5100, or 5190, or any of (ii-1) SEQ ID NO: 5010; (ii-2) SEQ ID NO: 5020; (ii-3) SEQ ID NO: 5030; (ii-4) SEQ ID NO: 5040; (ii-5) SEQ ID NO: 5050; (ii-6) SEQ ID NO: 5060; (ii-7) SEQ ID NO: 5070; (ii-8) SEQ ID NO: 5080; (ii-9) SEQ ID NO: 5090; (ii-10) SEQ ID NO: 5100; (ii-11) SEQ ID NO: 5110; (ii-12) SEQ ID NO: 5120; (ii-13) SEQ ID NO: 5130; (ii-14) SEQ ID NO: 5140; (ii-15) SEQ ID NO: 5150; (ii-16) SEQ ID NO: 5160; (ii-17) SEQ ID NO: 5170; (ii-18) SEQ ID NO: 5180; (ii-19) SEQ ID NO: 5190; (ii-20) SEQ ID NO: 5200; (ii-21) SEQ ID NO: 5210; (ii-22) SEQ ID NO: 5220; (ii-23) SEQ ID NO: 5230; (ii-24) SEQ ID NO: 5240; (ii-25) SEQ ID NO: 5250; (ii-26) SEQ ID NO: 5260; (ii-27) SEQ ID NO: 5270; (ii-28) SEQ ID NO: 5280; (ii-29) SEQ ID NO: 5290; (ii-30) SEQ ID NO: 5300; (ii-31) SEQ ID NO: 5310; (ii-32) SEQ ID NO: 5320; (ii-33) SEQ ID NO: 5330; or (ii-34) SEQ ID NO: 5340; 395SEQ ID NO: 6040, 6010, 6190, or 6270, or any of (iii-1) SEQ ID NO: 6010; (iii- 2) SEQ ID NO: 6020; (iii-3) SEQ ID NO: 6030; (iii-4) SEQ ID NO: 6040; (iii-5) SEQ ID NO: 6050; (iii-6) SEQ ID NO: 6060; (iii-7) SEQ ID NO: 6070; (iii-8) SEQ ID NO: 6080; (iii-9) SEQ ID NO: 6090; (iii-10) SEQ ID NO: 6100; (iii-11) SEQ ID NO: 6110; (iii-12) SEQ ID NO: 6120; (iii-13) SEQ ID NO: 6130; (iii-14) SEQ ID NO: 6140; (iii-15) SEQ ID NO: 6150; (iii-16) SEQ ID NO: 6160; (iii-17) SEQ ID NO: 6170; (iii-18) SEQ ID NO: 6180; (iii-19) SEQ ID NO: 6190; (iii-20) SEQ ID NO: 6200; (iii-21) SEQ ID NO: 6210; (iii-22) SEQ ID NO: 6220; (iii-23) SEQ ID NO: 6230; (iii-24) SEQ ID NO: 6240; (iii-25) SEQ ID NO: 6250; (iii-26) SEQ ID NO: 6260; (iii-27) SEQ ID NO: 6270; (iii-28) SEQ ID NO: 6280; (iii-29) SEQ ID NO: 6290; (iii-30) SEQ ID NO: 6300; (iii-31) SEQ ID NO: 6310; (iii-32) SEQ ID NO: 6320; (iii-33) SEQ ID NO: 6330; (iii-34) SEQ ID NO: 6340; (iii-35) SEQ ID NO: 6350; (iii-36) SEQ ID NO: 6360; (iii-37) SEQ ID NO: 6370; (iii-38) SEQ ID NO: 6380; (iii-39) SEQ ID NO: 6390; (iii-40) SEQ ID NO: 6400; (iii-41) SEQ ID NO: 6410; (iii-42) SEQ ID NO: 6420; (iii-43) SEQ ID NO: 6430; (iii-44) SEQ ID NO: 6440; (iii-45) SEQ ID NO: 6450; (iii-46) SEQ ID NO: 6460; (iii-47) SEQ ID NO: 6470; or (iii-48) SEQ ID NO: 6480; SEQ ID NO: 7010, 7060, 7130, or 7160, or any of (iv-1) SEQ ID NO: 7010; (iv-2) SEQ ID NO: 7020; (iv-3) SEQ ID NO: 7030; (iv-4) SEQ ID NO: 7040; (iv-5) SEQ ID NO: 7050; (iv-6) SEQ ID NO: 7060; (iv-7) SEQ ID NO: 7070; (iv-8) SEQ ID NO: 7080; (iv-9) SEQ ID NO: 7090; (iv-10) SEQ ID NO: 7100; (iv-11) SEQ ID NO: 7110; (iv-12) SEQ ID NO: 7120; (iv-13) SEQ ID NO: 7130; (iv-14) SEQ ID NO: 7140; (iv-15) SEQ ID NO: 7150; (iv-16) SEQ ID NO: 7160; (iv-17) SEQ ID NO: 7170; (iv-18) SEQ ID NO: 7180; (iv-19) SEQ ID NO: 7190; (iv-20) SEQ ID NO: 7200; (iv-21) SEQ ID NO: 7210; (iv-22) SEQ ID NO: 7220; (iv-23) SEQ ID NO: 7230; (iv-24) SEQ ID NO: 7240; (iv-25) SEQ ID NO: 7250; (iv-26) SEQ ID NO: 7260; (iv-27) SEQ ID NO: 7270; (iv-28) SEQ ID NO: 7280; or (iv- 29) SEQ ID NO: 7290; SEQ ID NO: 8030 or 8290, or any of (v-1) SEQ ID NO: 8010; (v-2) SEQ ID NO: 8020; (v-3) SEQ ID NO: 8030; (v-4) SEQ ID NO: 8040; (v-5) SEQ ID NO: 8050; (v-6) SEQ ID NO: 8060; (v-7) SEQ ID NO: 8070; (v-8) SEQ ID NO: 8080; (v-9) SEQ ID NO: 8090; (v-10) SEQ ID NO: 8100; (v-11) SEQ ID NO: 8110; (v-12) SEQ ID NO: 8120; (v-13) SEQ ID NO: 8130; (v-14) SEQ ID NO: 8140; (v-15) 396SEQ ID NO: 8150; (v-16) SEQ ID NO: 8160; (v-17) SEQ ID NO: 8170; (v-18) SEQ ID NO: 8180; (v-19) SEQ ID NO: 8190; (v-20) SEQ ID NO: 8200; (v-21) SEQ ID NO: 8210; (v-22) SEQ ID NO: 8220; (v-23) SEQ ID NO: 8230; (v-24) SEQ ID NO: 8240; (v-25) SEQ ID NO: 8250; (v-26) SEQ ID NO: 8260; (v-27) SEQ ID NO: 8270; (v-28) SEQ ID NO: 8280; (v-29) SEQ ID NO: 8290; (v-30) SEQ ID NO: 8300; (v-31) SEQ ID NO: 8310; or (v-32) SEQ ID NO: 8320; or SEQ ID NO: 9030 or 9120, or any of (vi-1) SEQ ID NO: 9010; (vi-2) SEQ ID NO: 9020; (vi-3) SEQ ID NO: 9030; (vi-4) SEQ ID NO: 9040; (vi-5) SEQ ID NO: 9050; (vi-6) SEQ ID NO: 9060; (vi-7) SEQ ID NO: 9070; (vi-8) SEQ ID NO: 9080; (vi-9) SEQ ID NO: 9090; (vi-10) SEQ ID NO: 9100; (vi-11) SEQ ID NO: 9110; (vi-12) SEQ ID NO: 9120; (vi-13) SEQ ID NO: 9130; (vi-14) SEQ ID NO: 9140; (vi-15) SEQ ID NO: 9150; (vi-16) SEQ ID NO: 9160; (vi-17) SEQ ID NO: 9170; (vi-18) SEQ ID NO: 9180; (vi-19) SEQ ID NO: 9190; (vi-20) SEQ ID NO: 9200; (vi-21) SEQ ID NO: 9210; (vi-22) SEQ ID NO: 9220; (vi-23) SEQ ID NO: 9230; (vi-24) SEQ ID NO: 9240; (vi-25) SEQ ID NO: 9250; (vi-26) SEQ ID NO: 9260; (vi-27) SEQ ID NO: 9270; or (vi-28) SEQ ID NO: 9280; (2) SEQ ID NO: 2110, 410, 1410, 1510, 1910, 2210, 2510, or 2710, or any of (i) SEQ ID NOS: 110; (ii) SEQ ID NO: 210; (iii) SEQ ID NO: 310; (iv) SEQ ID NO: 410; (v) SEQ ID NO: 510; (vi) SEQ ID NO: 610; (vii) SEQ ID NO: 710; (viii) SEQ ID NO: 810; (ix) SEQ ID NO: 910; (x) SEQ ID NO: 1010; (xi) SEQ ID NO: 1110; (xii) SEQ ID NO: 1210; (xiii) SEQ ID NO: 1310; (xiv) SEQ ID NO: 1410; (xv) SEQ ID NO: 1510; (xvi) SEQ ID NO: 1610; (xvii) SEQ ID NO: 1710; (xviii) SEQ ID NO: 1810; (xix) SEQ ID NO: 1910; (xx) SEQ ID NO: 2010; (xxi) SEQ ID NO: 2110; (xxii) SEQ ID NO: 2210; (xxiii) SEQ ID NO: 2310; (xxiv) SEQ ID NO: 2410; (xxv) SEQ ID NO: 2510; (xxvi) SEQ ID NO: 2610; (xxvii) SEQ ID NO: 2710; (xxviii) SEQ ID NO: 2810; (xxix) SEQ ID NO: 2910; or (xxx) SEQ ID NO: 3010; and / or (3) (xxxi) SEQ ID NOS: 10110; (xxxii) SEQ ID NO: 10210; (xxxiii) SEQ ID NO: 10310; (xxxiv) SEQ ID NO: 10410; (xxxv) SEQ ID NO: 10510; (xxxvi) SEQ ID NO: 10610; (xxxvii) SEQ ID NO: 10710; (xxxviii) SEQ ID NO: 10810; (xxxix) SEQ ID NO: 10910; (xl) SEQ ID NO: 11010; (xli) SEQ ID NO: 11110; (xlii) SEQ ID NO: 11210; (xliii) SEQ ID NO: 11310; (xliv) SEQ ID NO: 11410; (xlv) 397SEQ ID NO: 11510; (xlvi) SEQ ID NO: 11610; (xlvii) SEQ ID NO: 11710; or (xlviii) SEQ ID NO: 11810; or (b) a variant thereof having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any of said VHH amino acid sequences.

6. The first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-5, wherein the VH-1 comprises: (a) a first heavy chain framework region (FR) 1 (FRH1-1); (b) a first heavy chain FR2 (FRH2-1); (c) a first heavy chain FR3 (FRH3-1); (d) a first heavy chain FR4 (FRH4-1); and wherein: (I) the VH-1is partially or fully humanized; (II) the VH-1is humanized except for the FRH2-1; (III) the VH-1is humanized and comprises one or more of F or Y at position 37, E or Q at position 44, and / or R at position 45, wherein the position is according to Kabat or Martin numbering, or F or Y at position 42, E or Q at position 49, and / or R at position 50, wherein the position is according to IMGT numbering; and / or (IV) the VH-1comprises one or more amino acid modifications selected from the following: (IV-1) E or Q at position 1; V or L at position 5; L or V at position 11; Q or K at position 13; P at position 14; G or R at position 16; R at position 19; A at position 23; A at position 24; F at position 27; V at position 37; E or V at position 46; W at position 47; S or A at position 49; A or V at position 60; T at position 68; I or V at position 69; N or D at position 73; S or A at position 74; T or S at position 77; L or V at position 78; S at position 82b; R at position 83; A, V, or P at position 84; E or D at position 85; V or L at position 89; A or V at position 93; R, K, or T at position 94; and / or L, T, or M at position 108, wherein the position is according to Kabat numbering, 398optionally wherein the VH-1 comprises at least one of: P at position 14; F at position 27; V at position 37; W at position 47; L at position 78; R at position 83; A at position 84; R or K at position 94; and / or L at position 108 according to Kabat numbering; (IV-2) E or Q at position 1; V or L at position 5; L or V at position 11; Q or K at position 13; P at position 14; G or R at position 16; R at position 19; A at position 23; A at position 24; F at position 27; V at position 37; E or V at position 46; W at position 47; S or A at position 49; A or V at position 60; T at position 68; I or V at position 69; N or D at position 72a; S or A at position 72b; T or S at position 74; L or V at position 75; S at position 81; R at position 83; A, V, or P at position 84; E or D at position 85; V or L at position 89; A or V at position 93; R, K, or T at position 94; and / or L, T, or M at position 108, wherein the position is according to Martin numbering, optionally wherein the VH-1 comprises at least one of: P at position 14; F at position 27; V at position 37; W at position 47; L at position 75; R at position 83; A at position 84; R or K at position 94; and / or L at position 108 according to Martin numbering; or (IV-3) E or Q at position 1; V or L at position 5; L or V at position 12; Q or K at position 14; P at position 15; G or R at position 17; R at position 20; A at position 24; A at position 25; F at position 28; V at position 42; E or V at position 51; W at position 52; S or A at position 54; A or V at position 68; T at position 77; I or V at position 78; N or D at position 82; S or A at position 83; T or S at position 86; L or V at position 87; S at position 93; R at position 95; A, V, or P at position 96; E or D at position 97; V or L at position 101; A or V at position 105; R, K, or T at position 106; and / or L, T, or M at position 123, wherein the position is according to IMGT numbering, optionally wherein the VH-1 comprises at least one of: P at position 15; F at position 28; V at position 42; W at position 52; L at position 87; R at position 95; A at position 96; R or K at position 106; and / or L at position 123, wherein the position is according to IMGT numbering; and / or (VI) (1) (i) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9412, 9414, and 9416, respectively, and: 399the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2X3SGX4X5X6X7X8X9GX10SX11X12X13SCX14ASG (SEQ ID NO: 9411), wherein X1 is Q or E; X2 is V or L; X3 is E or Q; X4 is G or A; X5 is G or E; X6 is L or V; X7 is V or K; X8 is Q or K; X9 is A or P; X10 is G, R, or S; X11 is L or V; X12 is R or K; X13 is L or V; and X14 is A or K; the amino acid sequence of the FRH2-1 comprises or consists of WX1RX2X3PGX4QREX5X6X7(SEQ ID NO: 9413), wherein X1 is Y or V; X2 is R or Q; X3 is V or A; X4 is K or Q; X5 is L or W; X6 is V or M; and X7 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1X2IX3X4DX5X6X7X8X9X10YX11X12X13X14SLX15X16EDTAVYX17C (SEQ ID NO: 9415), wherein X1 is F or V; X2 is A or T ; X3 is S or T; X4 is R or A; X5 is N or E; X6 is V, A, or S; X7 is Q, K, or T; X8 is N or S; X9 is Q, S, or T; X10 is V, L, or A; X11 is L or M; X12 is Q or E; X13 is M or L; X14 is N or S; X15 is K or R; X16 is P, A, or S; and X17 is F or Y; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9417), wherein X1 is Q or L; (ii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9422, 9424, and 9426, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of EVQLX1ESGGGLVQPGX2SLRLSCAASG (SEQ ID NO: 9421), wherein X1 is V or L; and X2 is G or R; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKQREX2VX3(SEQ ID NO: 9423), wherein X1 is Y or V; X2 is L or W; and X3 is A or S; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1X2NX3X4YLQMNSLRAEDTAVYX5C (SEQ ID NO: 9425), wherein X1 is S, V, or A; X2 is Q or K; X3 is T or S; X4 is V or L; and X5 is F or Y; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9427); or 400(iii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9432, 9434, and 9436, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9431); the amino acid sequence of the FRH2-1 comprises or consists of WYRQAPGQQRELMX1 (SEQ ID NO: 9433), wherein X1 is A or G; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9435), wherein X1 is A or R; X2 is E or N; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9437); (2) (i) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9512, 9514, and 9516, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2X3SX4X5X6X7X8X9PGX10SX11X12X13SCX14ASX15(SEQ ID NO: 9511), wherein X1 is E or Q; X2 is V or L; X3 is D, E, or Q; X4 is E or G; X5 is G or A; X6 is G or E; X7 is L or V; X8 is V or K; X9 is Q or K; X10 is G or S; X11 is L or V; X12 is R or K; X13 is L or V; X14 is V, A, or K; and X15 is A or G; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGX2EREX3X4X5(SEQ ID NO: 9513), wherein X1 is F or V; X2 is K or Q; X3 is F or W; X4 is V or M; and X5 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1TIX2X3DX4X5X6X7X8X9YX10X11X12X13X14LX15X16EDTAVYYC (SEQ ID NO: 9515), wherein X1 is F or V; X2 is A, S, or T; X3 is R or A; X4 is N or E; X5 is A or S; X6 is R, K, or T; X7 is S or N; X8 is T or S; X9 is V, L, or A; X10 is L or M; X11 is Q or E; X12 is M or L; X13 is D, N, or S; X14 is N or S; X15 is K or R; and X16 is P, A, or S; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGRGTX1VTVSX2(SEQ ID NO: 9517), wherein X1 is Q or L; and X2 is F or S; 401(ii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9522, 9524, and 9526, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2ESGGGLVX3PGGSLRLSCAASX4(SEQ ID NO: 9521), wherein X1 is Q or E; X2 is V or L; X3 is K or Q; and X4 is G or A; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKEREX2VX3(SEQ ID NO: 9523), wherein X1 is F or V; X2 is F or W; and X3 is S or A; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1KX2X3X4YLQMNSLRAEDTAVYYC (SEQ ID NO: 9525), wherein X1 is A or S; X2 is N or S; X3 is S or T; and X4 is L or V; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGRGTLVTVSS (SEQ ID NO: 9527); or (iii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9532, 9534, and 9536, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9531); the amino acid sequence of the FRH2-1 comprises or consists of WFRQAPGQEREFMX1(SEQ ID NO: 9533), wherein X1 is A or G; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9535), wherein X1 is A or R; X2 is E or N; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGRGTLVTVSS (SEQ ID NO: 9537); (3) (i) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9612, 9614, and 9616, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VX2LX3X4SGX5X6X7X8X9X10GX11SX12X13X14SCX15ASG (SEQ ID NO: 9611), wherein X1 is Q, E; X2 is H, Q; X3 is V, L; X4 is E, Q; X5 is G, A; X6 402is G, E; X7 is L, V; X8 is V, K; X9 is Q, K; X10 is A, P; X11 is G, R, S; X12 is L, V;X13 is R, K; X14 is L, V; and X15 is A, K; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGX2QRX3X4X5X6(SEQ ID NO: 9613), wherein X1 is Y or V; X2 is K or Q; X3 is D or E; X4 is F or W; X5 is V or M; and X6 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1TIX2X3DX4X5X6X7X8X9YX10X11X12X13SLX14X15EDTAVYYC (SEQ ID NO: 9615), wherein X1 is F or V; X2 is S or T; X3 is R or A; X4 is N or E; X5 is A or S; X6 is K or T; X7 is N or S; X8 is T or S; X9 is V, L, or A; X10 is L or M; X11 is Q or E; X12 is M or L; X13 is N or S; X14 is K or R; and X15 is P, A, or S; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9617), wherein X1 is Q or L; (ii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9622, 9624, and 9626, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2ESGGGLVX3PGX4SLRLSCAASG (SEQ ID NO: 9621), wherein X1 is Q or E; X2 is V or L; X3 is K or Q; and X4 is G or R; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKQRX2X3VX4(SEQ ID NO: 9623), wherein X1 is Y or V; X2 is D or E; X3 is F or W; and X4 is A or S; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1KNX2X3YLQMNSLX4X5EDTAVYYC (SEQ ID NO: 9625), wherein X1 is A or S; X2 is S or T; X3 is V or L; X4 is R or K; and X5 is P or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9627); or (iii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9632, 9634, and 9636, respectively, and: 403the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9631); the amino acid sequence of the FRH2-1 comprises or consists of WYRQAPGQQREFMX1(SEQ ID NO: 9633), wherein X1 is G or A; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9635), wherein X1 is A or R; X2 is E or N; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9637); (4) (i) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9712, 9714, and 9716, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2X3SGX4X5X6X7X8PGX9SX10X11X12SCX13ASG (SEQ ID NO: 9711), wherein X1 is E or Q; X2 is V or L; X3 is E or Q; X4 is G or A; X5 is G or E; X6 is S, L, or V; X7 is V or K; X8 is Q or K; X9 is G, R, or S; X10 is L or V; X11 is R or K; X12 is L or V; and X13 is L, A, or K; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGX2EREFX3X4(SEQ ID NO: 9713), wherein X1 is F or V; X2 is K or Q; X3 is V or M; and X4 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1TIX2X3DX4X5X6X7X8X9YX10X11X12X13SLX14X15EDTAX16YYC (SEQ ID NO: 9715), wherein X1 is F or V; X2 is S or T; X3 is R or A; X4 is N or E; X5 is A or S; X6 is R, K, or T; X7 is T, N, or S; X8 is T or S; X9 is V, L, or A; X10 is L or M; X11 is R, Q, or E; X12 is M or L; X13 is D, N, or S; X14 is K or R; X15 is P, A, or S; and X16 is I or V; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9717), wherein X1 is Q or L; (ii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9722, 9724, and 9726, respectively, and: 404the amino acid sequence of the FRH1-1 comprises or consists of EVQLX1ESGGGLVQPGX2SLRLSCAASG (SEQ ID NO: 9721), wherein X1 is L or V; and X2 is G or R; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKEREFVX2(SEQ ID NO: 9723), wherein X1 is F or V; and X2 is S or A; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1X2X3X4X5YLQMNSLRX6EDTAVYYC (SEQ ID NO: 9725), wherein X1 is S or A; X2 is K or R; X3 is N or T; X4 is T or S; X5 is V or L; and X6 is A or P; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9727); or (iii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9732, 9734, and 9736, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9731); the amino acid sequence of the FRH2-1 comprises or consists of WFRQAPGQEREFMX1(SEQ ID NO: 9733), wherein X1 is A or G; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9735), wherein X1 is A or R; X2 is E or N; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9737); (5) (i) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9812, 9814, and 9816, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2X3SGX4X5X6X7X8X9GX10SX11X12X13SCX14ASG (SEQ ID NO: 9811), wherein X1 is E or Q; X2 is V or L; X3 is E or Q; X4 is G or A; X5 is G or E; X6 is L or V; X7 is V or K; X8 is Q or K; X9 is A or P; X10 is G, R, or S; X11 is L or V; X12 is R or K; X13 is L or V; and X14 is E, A, or K; 405the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGX2EREFX3X4(SEQ ID NO: 9813), wherein X1 is F or V; X2 is K or Q; X3 is V or M; and X4 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1TIX2X3DX4X5X6X7X8X9YX10X11X12X13SLX14X15EDTAX16YYC (SEQ ID NO: 9815), wherein X1 is F or V; X2 is T or S; X3 is R or A; X4 is N or E; X5 is A or S; X6 is K or T; X7 is K, N, or S; X8 is V, S, or T; X9 is V, L, or A; X10 is L or M; X11 is Q or E; X12 is M or L; X13 is S or N;X14 is K or R; X15 is P, A, or S; and X16 is A, V, or L; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9817), wherein X1 is Q, L, or T; (ii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9822, 9824, and 9826, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of EVQLX1ESGGGLVQPGX2SLRLSCAASG (SEQ ID NO: 9821), wherein X1 is V or L; and X2 is R or G; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKEREFVX2(SEQ ID NO: 9823), wherein X1 is V or F; and X2 is S or A; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1KX2X3X4YLQMNSLX5X6EDTAX7YYC (SEQ ID NO: 9825), wherein X1 is A or S; X2 is N or K; X3 is S or T; X4 is V or L; X5 is R or K; X6 is A or P; and X7 is V or L; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9827), wherein X1 is L or T; or (iii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9832, 9834, and 9836, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9831); 406the amino acid sequence of the FRH2-1 comprises or consists of WFRQAPGQEREFMX1(SEQ ID NO: 9833), wherein X1 is G or A; the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9835), wherein X1 is A or R; X2 is E or N; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9837); or (6) (i) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9912, 9914, and 9916, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of X1VQLX2X3SX4X5X6X7X8X9X10GX11SX12X13X14SCX15ASG (SEQ ID NO: 9911), wherein X1 is E or Q; X2 is V or L; X3 is E or Q; X4 is K or G; X5 is G or A; X6 is G or E; X7 is L or V; X8 is V or K; X9 is Q or K; X10 is F or P; X11 is G or S; X12 is L or V; X13 is N, R, or K;X14 is L or V; and X15 is A, S, or K; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGX2EREFX3X4(SEQ ID NO: 9913), wherein X1 is F or V; X2 is K or Q; X3 is V or M; and X4 is A, S, or G; the amino acid sequence of the FRH3-1 comprises or consists of RX1X2IX3X4DX5X6X7X8X9X10YX11X12X13X14SLX15X16EDTAVYYC (SEQ ID NO: 9915), wherein X1 is F or V; X2 is I or T; X3 is S or T; X4 is R or A; X5 is N or E; X6 is A or S; X7 is K or T; X8 is N or S; X9 is T or S; X10 is V, L, or A; X11 is L or M; X12 is Q or E; X13 is M or L;X14 is S or N; X15 is K or R; and X16 is P, A, or S; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTX1VTVSS (SEQ ID NO: 9917), wherein X1 is Q or L; (ii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9922, 9924, and 9926, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of EVQLLESGGGLVQPGGSLRLSCAASG (SEQ ID NO: 9921); 407the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKEREFVX2(SEQ ID NO: 9923), wherein X1 is F or V; and X2 is A or S; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1KNTX2YLQMNSLX3X4EDTAVYYC (SEQ ID NO: 9925), wherein X1 is A or S; X2 is V or L; X3 is R or K; and X4 is A or P; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9927); (iii) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9932, 9934, and 9936, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of EVQLX1ESGGGLVQPGGSLRLSCX2ASG (SEQ ID NO: 9931), wherein X1 is L or V; and X2 is A or S; the amino acid sequence of the FRH2-1 comprises or consists of WX1RQAPGKEREFVX2(SEQ ID NO: 9933), wherein X1 is F or V; and X2 is A or S; the amino acid sequence of the FRH3-1 comprises or consists of RFTISRDNX1KNX2X3YLQMX4SLX5X6EDTAVYYC (SEQ ID NO: 9935), wherein X1 is A or S; X2 is T or S; X3 is V or L; X4 is N or S; X5 is R or K; and X6 is A or P; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9937); or (iv) the amino acid sequences of the CDRH1-1, the CDRH2-1, and the CDRH3-1 comprise or consist of SEQ ID NO: 9942, 9944, and 9946, respectively, and: the amino acid sequence of the FRH1-1 comprises or consists of QVQLVQSGAEVKKPGSSVKVSCKASG (SEQ ID NO: 9941); the amino acid sequence of the FRH2-1 comprises or consists of WFRQAPGQEREFMX1(SEQ ID NO: 9943), wherein X1 is A or G; 408the amino acid sequence of the FRH3-1 comprises or consists of RVTITX1DX2STSTX3YMELSSLRSEDTAVYYC (SEQ ID NO: 9945), wherein X1 is R or A; X2 is N or E; and X3 is V or A; and / or the amino acid sequence of the FRH4-1 comprises or consists of WGQGTLVTVSS (SEQ ID NO: 9947).

7. The first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-6, wherein: (1) the anti-human CD3 antibody or antigen-binding antibody fragment is one according to claim 2 or 3, and the amino acid sequence of the VH-1 is the same as the VHH amino acid sequence of said anti-CD3 antibody listed in Table 13A, or listed in Table 1A or 24A except that the VH-1 comprises at least one of said one or more amino acid modifications; and / or (2) the anti-human CD3 antibody or antigen-binding antibody fragment is according to claim 4 or 5, wherein the amino acid sequences of the FRH1-1, the FRH2-1, the FRH3-1, and the FRH4-1 comprise or consist of: (a) the FR1, FR2, FR3, and FR4 amino acid sequences, respectively, contained in the VHH amino acid sequence of: (1) SEQ ID NO: 4140 or any of (i-1) SEQ ID NO: 4010; (i-2) SEQ ID NO: 4020; (i-3) SEQ ID NO: 4030; (i-4) SEQ ID NO: 4040; (i-5) SEQ ID NO: 4050; (i-6) SEQ ID NO: 4060; (i-7) SEQ ID NO: 4070; (i-8) SEQ ID NO: 4080; (i-9) SEQ ID NO: 4090; (i-10) SEQ ID NO: 4100; (i-11) SEQ ID NO: 4110; (i-12) SEQ ID NO: 4120; (i-13) SEQ ID NO: 4130; (i-14) SEQ ID NO: 4140; (i-15) SEQ ID NO: 4150; (i-16) SEQ ID NO: 4160; (i-17) SEQ ID NO: 4170; (i-18) SEQ ID NO: 4180; (i-19) SEQ ID NO: 4190; (i- 20) SEQ ID NO: 4200; (i-21) SEQ ID NO: 4210; (i-22) SEQ ID NO: 4220; (i-23) SEQ ID NO: 4230; (i-24) SEQ ID NO: 4240; (i-25) SEQ ID NO: 4250; (i-26) SEQ ID NO: 4260; (i-27) SEQ ID NO: 4270; (i-28) SEQ ID NO: 4280; (i-29) SEQ ID NO: 4290; (i-30) SEQ ID NO: 4300; (i-31) SEQ ID NO: 4310; (i-32) SEQ ID NO: 4320; (i-33) SEQ ID NO: 4330; (i- 40934) SEQ ID NO: 4340; (i-35) SEQ ID NO: 4350; (i-36) SEQ ID NO: 4360; (i-37) SEQ ID NO: 4370; (i-38) SEQ ID NO: 4380; (i-39) SEQ ID NO: 4390; (i-40) SEQ ID NO: 4400; (i-41) SEQ ID NO: 4410; (i-42) SEQ ID NO: 4420; (i-43) SEQ ID NO: 4430; or (i-44) SEQ ID NO: 4440; SEQ ID NO: 5100, 5010, or 5190, or any of (ii-1) SEQ ID NO: 5010; (ii- 2) SEQ ID NO: 5020; (ii-3) SEQ ID NO: 5030; (ii-4) SEQ ID NO: 5040; (ii-5) SEQ ID NO: 5050; (ii-6) SEQ ID NO: 5060; (ii-7) SEQ ID NO: 5070; (ii-8) SEQ ID NO: 5080; (ii-9) SEQ ID NO: 5090; (ii-10) SEQ ID NO: 5100; (ii-11) SEQ ID NO: 5110; (ii-12) SEQ ID NO: 5120; (ii-13) SEQ ID NO: 5130; (ii-14) SEQ ID NO: 5140; (ii-15) SEQ ID NO: 5150; (ii-16) SEQ ID NO: 5160; (ii-17) SEQ ID NO: 5170; (ii-18) SEQ ID NO: 5180; (ii-19) SEQ ID NO: 5190; (ii-20) SEQ ID NO: 5200; (ii-21) SEQ ID NO: 5210; (ii-22) SEQ ID NO: 5220; (ii-23) SEQ ID NO: 5230; (ii-24) SEQ ID NO: 5240; (ii-25) SEQ ID NO: 5250; (ii-26) SEQ ID NO: 5260; (ii-27) SEQ ID NO: 5270; (ii-28) SEQ ID NO: 5280; (ii-29) SEQ ID NO: 5290; (ii-30) SEQ ID NO: 5300; (ii-31) SEQ ID NO: 5310; (ii-32) SEQ ID NO: 5320; (ii-33) SEQ ID NO: 5330; or (ii-34) SEQ ID NO: 5340; SEQ ID NO: 6040, 6010, 6190, or 6270, or any of (iii-1) SEQ ID NO: 6010; (iii-2) SEQ ID NO: 6020; (iii-3) SEQ ID NO: 6030; (iii-4) SEQ ID NO: 6040; (iii-5) SEQ ID NO: 6050; (iii-6) SEQ ID NO: 6060; (iii-7) SEQ ID NO: 6070; (iii-8) SEQ ID NO: 6080; (iii-9) SEQ ID NO: 6090; (iii-10) SEQ ID NO: 6100; (iii-11) SEQ ID NO: 6110; (iii-12) SEQ ID NO: 6120; (iii-13) SEQ ID NO: 6130; (iii-14) SEQ ID NO: 6140; (iii-15) SEQ ID NO: 6150; (iii-16) SEQ ID NO: 6160; (iii-17) SEQ ID NO: 6170; (iii-18) SEQ ID NO: 6180; (iii-19) SEQ ID NO: 6190; (iii-20) SEQ ID NO: 6200; (iii-21) SEQ ID NO: 6210; (iii-22) SEQ ID NO: 6220; (iii-23) SEQ ID NO: 6230; (iii-24) SEQ ID NO: 6240; (iii-25) SEQ ID NO: 6250; (iii-26) SEQ ID NO: 6260; (iii-27) SEQ ID NO: 6270; (iii-28) SEQ ID NO: 6280; (iii-29) SEQ ID NO: 6290; (iii-30) SEQ ID NO: 6300; (iii-31) SEQ ID NO: 6310; (iii-32) SEQ ID NO: 6320; (iii-33) SEQ ID NO: 6330; (iii-34) SEQ ID NO: 6340; (iii-35) SEQ ID NO: 6350; (iii-36) SEQ ID NO: 6360; (iii-37) SEQ ID NO: 6370; (iii-38) SEQ ID NO: 6380; (iii-39) SEQ ID NO: 6390; (iii-40) SEQ ID NO: 6400; (iii-41) SEQ ID NO: 6410; (iii-42) 410SEQ ID NO: 6420; (iii-43) SEQ ID NO: 6430; (iii-44) SEQ ID NO: 6440; (iii-45) SEQ ID NO: 6450; (iii-46) SEQ ID NO: 6460; (iii-47) SEQ ID NO: 6470; or (iii-48) SEQ ID NO: 6480; SEQ ID NO: 7010, 7060, 7130, or 7160, or any of (iv-1) SEQ ID NO: 7010; (iv-2) SEQ ID NO: 7020; (iv-3) SEQ ID NO: 7030; (iv-4) SEQ ID NO: 7040; (iv-5) SEQ ID NO: 7050; (iv-6) SEQ ID NO: 7060; (iv-7) SEQ ID NO: 7070; (iv-8) SEQ ID NO: 7080; (iv-9) SEQ ID NO: 7090; (iv-10) SEQ ID NO: 7100; (iv-11) SEQ ID NO: 7110; (iv-12) SEQ ID NO: 7120; (iv-13) SEQ ID NO: 7130; (iv-14) SEQ ID NO: 7140; (iv-15) SEQ ID NO: 7150; (iv-16) SEQ ID NO: 7160; (iv-17) SEQ ID NO: 7170; (iv-18) SEQ ID NO: 7180; (iv-19) SEQ ID NO: 7190; (iv-20) SEQ ID NO: 7200; (iv-21) SEQ ID NO: 7210; (iv-22) SEQ ID NO: 7220; (iv-23) SEQ ID NO: 7230; (iv-24) SEQ ID NO: 7240; (iv-25) SEQ ID NO: 7250; (iv-26) SEQ ID NO: 7260; (iv-27) SEQ ID NO: 7270; (iv-28) SEQ ID NO: 7280; or (iv-29) SEQ ID NO: 7290; SEQ ID NO: 8030 or 8290, or any of (v-1) SEQ ID NO: 8010; (v-2) SEQ ID NO: 8020; (v-3) SEQ ID NO: 8030; (v-4) SEQ ID NO: 8040; (v-5) SEQ ID NO: 8050; (v-6) SEQ ID NO: 8060; (v-7) SEQ ID NO: 8070; (v- 8) SEQ ID NO: 8080; (v-9) SEQ ID NO: 8090; (v-10) SEQ ID NO: 8100; (v-11) SEQ ID NO: 8110; (v-12) SEQ ID NO: 8120; (v-13) SEQ ID NO: 8130; (v-14) SEQ ID NO: 8140; (v-15) SEQ ID NO: 8150; (v-16) SEQ ID NO: 8160; (v-17) SEQ ID NO: 8170; (v-18) SEQ ID NO: 8180; (v-19) SEQ ID NO: 8190; (v-20) SEQ ID NO: 8200; (v-21) SEQ ID NO: 8210; (v-22) SEQ ID NO: 8220; (v-23) SEQ ID NO: 8230; (v-24) SEQ ID NO: 8240; (v-25) SEQ ID NO: 8250; (v-26) SEQ ID NO: 8260; (v-27) SEQ ID NO: 8270; (v-28) SEQ ID NO: 8280; (v-29) SEQ ID NO: 8290; (v-30) SEQ ID NO: 8300; (v-31) SEQ ID NO: 8310; or (v-32) SEQ ID NO: 8320; or SEQ ID NO: 9030 or 9120, or any of (vi-1) SEQ ID NO: 9010; (vi-2) SEQ ID NO: 9020; (vi-3) SEQ ID NO: 9030; (vi-4) SEQ ID NO: 9040; (vi-5) SEQ ID NO: 9050; (vi-6) SEQ ID NO: 9060; (vi-7) SEQ ID NO: 9070; (vi-8) SEQ ID NO: 9080; (vi-9) SEQ ID NO: 9090; (vi-10) SEQ ID NO: 9100; (vi-11) SEQ ID NO: 9110; (vi-12) SEQ ID NO: 9120; (vi-13) SEQ 411ID NO: 9130; (vi-14) SEQ ID NO: 9140; (vi-15) SEQ ID NO: 9150; (vi- 16) SEQ ID NO: 9160; (vi-17) SEQ ID NO: 9170; (vi-18) SEQ ID NO: 9180; (vi-19) SEQ ID NO: 9190; (vi-20) SEQ ID NO: 9200; (vi-21) SEQ ID NO: 9210; (vi-22) SEQ ID NO: 9220; (vi-23) SEQ ID NO: 9230; (vi- 24) SEQ ID NO: 9240; (vi-25) SEQ ID NO: 9250; (vi-26) SEQ ID NO: 9260; (vi-27) SEQ ID NO: 9270; or (vi-28) SEQ ID NO: 9280; (2) SEQ ID NO: 410, 1410, 1510, 1910, 2110, 2210, 2510, or 2710, or any of (i) SEQ ID NOS: 110; (ii) SEQ ID NO: 210; (iii) SEQ ID NO: 310; (iv) SEQ ID NO: 410; (v) SEQ ID NO: 510; (vi) SEQ ID NO: 610; (vii) SEQ ID NO: 710; (viii) SEQ ID NO: 810; (ix) SEQ ID NO: 910; (x) SEQ ID NO: 1010; (xi) SEQ ID NO: 1110; (xii) SEQ ID NO: 1210; (xiii) SEQ ID NO: 1310; (xiv) SEQ ID NO: 1410; (xv) SEQ ID NO: 1510; (xvi) SEQ ID NO: 1610; (xvii) SEQ ID NO: 1710; (xviii) SEQ ID NO: 1810; (xix) SEQ ID NO: 1910; (xx) SEQ ID NO: 2010; (xxi) SEQ ID NO: 2110; (xxii) SEQ ID NO: 2210; (xxiii) SEQ ID NO: 2310; (xxiv) SEQ ID NO: 2410; (xxv) SEQ ID NO: 2510; (xxvi) SEQ ID NO: 2610; (xxvii) SEQ ID NO: 2710; (xxviii) SEQ ID NO: 2810; (xxix) SEQ ID NO: 2910; or (xxx) SEQ ID NO: 3010, except that the VH-1 comprises at least one of said one or more amino acid modifications; or (3) (xxxi) SEQ ID NOS: 10110; (xxxii) SEQ ID NO: 10210; (xxxiii) SEQ ID NO: 10310; (xxxiv) SEQ ID NO: 10410; (xxxv) SEQ ID NO: 10510; (xxxvi) SEQ ID NO: 10610; (xxxvii) SEQ ID NO: 10710; (xxxviii) SEQ ID NO: 10810; (xxxix) SEQ ID NO: 10910; (xl) SEQ ID NO: 11010; (xli) SEQ ID NO: 11110; (xlii) SEQ ID NO: 11210; (xliii) SEQ ID NO: 11310; (xliv) SEQ ID NO: 11410; (xlv) SEQ ID NO: 11510; (xlvi) SEQ ID NO: 11610; (xlvii) SEQ ID NO: 11710; or (xlviii) SEQ ID NO: 11810; and / or (b) the FR1, FR2, FR3, and FR4 amino acid sequences of: (1) SEQ ID NO: 3901, wherein X1is E or Q, X2is V or L, X3is E or Q, X4is G or A, X5is G or E, X6is L or V, X7is V or K, X8is Q or K, X9is G, R, or S, X10is L or V, X11is R or K, X12is L or V, X13is A, K, or S, and X14is G or A, 412SEQ ID NO: 3903, wherein X1is Y, V, or F, X2is K or Q, X3is Q or E, X4is E or D, X5is L, W, or F, X6is V or M, and X7is A, S, or G, SEQ ID NO: 3905, wherein X1is F or V, X2is S or T, X3is R or A, X4is N or E, X5is A, S, or V, X6is Q, K, T, or R, X7is N, S, T, or K, X8is S or T, X9is V, L, or A, X10is L or M, X11is Q or E, X12is M or L, X13is N or S, X14is R or K, X15is A, S, or P, X16is V or L, and X17is F or Y, and SEQ ID NO: 3907, wherein X1is Q or R, respectively; or SEQ ID NOS: 4141, 4143, 4145, and 4147, respectively, or any of (i-1) SEQ ID NOS: 4011, 4013, 4015, and 4017, respectively; (i-2) SEQ ID NOS: 4021, 4023, 4025, and 4027, respectively; (i-3) SEQ ID NOS: 4031, 4033, 4035, and 4037, respectively; (i-4) SEQ ID NOS: 4041, 4043, 4045, and 4047, respectively; (i-5) SEQ ID NOS: 4051, 4053, 4055, and 4057, respectively; (i-6) SEQ ID NOS: 4061, 4063, 4065, and 4067, respectively; (i-7) SEQ ID NOS: 4071, 4073, 4075, and 4077, respectively; (i-8) SEQ ID NOS: 4081, 4083, 4085, and 4087, respectively; (i-9) SEQ ID NOS: 4091, 4093, 4095, and 4097, respectively; (i-10) SEQ ID NOS: 4101, 4103, 4105, and 4107, respectively; (i-11) SEQ ID NOS: 4111, 4113, 4115, and 4117, respectively; (i-12) SEQ ID NOS: 4121, 4123, 4125, and 4127, respectively; (i-13) SEQ ID NOS: 4131, 4133, 4135, and 4137, respectively; (i-14) SEQ ID NOS: 4141, 4143, 4145, and 4147, respectively; (i-15) SEQ ID NOS: 4151, 4153, 4155, and 4157, respectively; (i-16) SEQ ID NOS: 4161, 4163, 4165, and 4167, respectively; (i-17) SEQ ID NOS: 4171, 4173, 4175, and 4177, respectively; (i-18) SEQ ID NOS: 4181, 4183, 4185, and 4187, respectively; (i-19) SEQ ID NOS: 4191, 4193, 4195, and 4197, respectively; (i-20) SEQ ID NOS: 4201, 4203, 4205, and 4207, respectively; (i-21) SEQ ID NOS: 4211, 4213, 4215, and 4217, respectively; (i-22) SEQ ID NOS: 4221, 4223, 4225, and 4227, respectively; (i-23) SEQ ID NOS: 4231, 4233, 4235, and 4237, respectively; (i-24) SEQ ID NOS: 4241, 4243, 4245, and 4247, respectively; (i-25) SEQ ID NOS: 4251, 4253, 4255, and 4257, respectively; (i-26) SEQ ID NOS: 4261, 4263, 4265, and 4267, 413respectively; (i-27) SEQ ID NOS: 4271, 4273, 4275, and 4277, respectively; (i-28) SEQ ID NOS: 4281, 4283, 4285, and 4287, respectively; (i-29) SEQ ID NOS: 4291, 4293, 4295, and 4297, respectively; (i-30) SEQ ID NOS: 4301, 4303, 4305, and 4307, respectively; (i-31) SEQ ID NOS: 4311, 4313, 4315, and 4317, respectively; (i-32) SEQ ID NOS: 4321, 4323, 4325, and 4327, respectively; (i-33) SEQ ID NOS: 4331, 4333, 4335, and 4337, respectively; (i-34) SEQ ID NOS: 4341, 4343, 4345, and 4347, respectively; (i-35) SEQ ID NOS: 4351, 4353, 4355, and 4357, respectively; (i-36) SEQ ID NOS: 4361, 4363, 4365, and 4367, respectively; (i-37) SEQ ID NOS: 4371, 4373, 4375, and 4377, respectively; (i-38) SEQ ID NOS: 4381, 4383, 4385, and 4387, respectively; (i-39) SEQ ID NOS: 4391, 4393, 4395, and 4397, respectively; (i-40) SEQ ID NOS: 4401, 4403, 4405, and 4407, respectively; (i-41) SEQ ID NOS: 4411, 4413, 4415, and 4417, respectively; (i-42) SEQ ID NOS: 4421, 4423, 4425, and 4427, respectively; (i-43) SEQ ID NOS: 4431, 4433, 4435, and 4437, respectively; or (i-44) SEQ ID NOS: 4441, 4443, 4445, and 4447, respectively; SEQ ID NOS: 5011, 5013, 5015, and 5017, respectively, SEQ ID NOS: 5101, 5103, 5105, and 5107, respectively, or SEQ ID NOS: 5191, 5193, 5195, and 5197, respectively, or any of (ii-1) SEQ ID NOS: 5011, 5013, 5015, and 5017, respectively; (ii-2) SEQ ID NOS: 5021, 5023, 5025, and 5027, respectively; (ii-3) SEQ ID NOS: 5031, 5033, 5035, and 5037, respectively; (ii-4) SEQ ID NOS: 5041, 5043, 5045, and 5047, respectively; (ii-5) SEQ ID NOS: 5051, 5053, 5055, and 5057, respectively; (ii-6) SEQ ID NOS: 5061, 5063, 5065, and 5067, respectively; (ii-7) SEQ ID NOS: 5071, 5073, 5075, and 5077, respectively; (ii-8) SEQ ID NOS: 5081, 5083, 5085, and 5087, respectively; (ii-9) SEQ ID NOS: 5091, 5093, 5095, and 5097, respectively; (ii-10) SEQ ID NOS: 5101, 5103, 5105, and 5107, respectively; (ii-11) SEQ ID NOS: 5111, 5113, 5115, and 5117, respectively; (ii-12) SEQ ID NOS: 5121, 5123, 5125, and 5127, 414respectively; (ii-13) SEQ ID NOS: 5131, 5133, 5135, and 5137, respectively; (ii-14) SEQ ID NOS: 5141, 5143, 5145, and 5147, respectively; (ii-15) SEQ ID NOS: 5151, 5153, 5155, and 5157, respectively; (ii-16) SEQ ID NOS: 5161, 5163, 5165, and 5167, respectively; (ii-17) SEQ ID NOS: 5171, 5173, 5175, and 5177, respectively; (ii-18) SEQ ID NOS: 5181, 5183, 5185, and 5187, respectively; (ii-19) SEQ ID NOS: 5191, 5193, 5195, and 5197, respectively; (ii-20) SEQ ID NOS: 5201, 5203, 5205, and 5207, respectively; (ii-21) SEQ ID NOS: 5211, 5213, 5215, and 5217, respectively; (ii-22) SEQ ID NOS: 5221, 5223, 5225, and 5227, respectively; (ii-23) SEQ ID NOS: 5231, 5233, 5235, and 5237, respectively; (ii-24) SEQ ID NOS: 5241, 5243, 5245, and 5247, respectively; (ii-25) SEQ ID NOS: 5251, 5253, 5255, and 5257, respectively; (ii-26) SEQ ID NOS: 5261, 5263, 5265, and 5267, respectively; (ii-27) SEQ ID NOS: 5271, 5273, 5275, and 5277, respectively; (ii-28) SEQ ID NOS: 5281, 5283, 5285, and 5287, respectively; (ii-29) SEQ ID NOS: 5291, 5293, 5295, and 5297, respectively; (ii-30) SEQ ID NOS: 5301, 5303, 5305, and 5307, respectively; (ii-31) SEQ ID NOS: 5311, 5313, 5315, and 5317, respectively; (ii-32) SEQ ID NOS: 5321, 5323, 5325, and 5327, respectively; (ii-33) SEQ ID NOS: 5331, 5333, 5335, and 5337, respectively; or (ii-34) SEQ ID NOS: 5341, 5343, 5345, and 5347, respectively; SEQ ID NOS: 6041, 6043, 6045, and 6047, respectively, SEQ ID NOS: 6011, 6013, 6015, and 6017, respectively, SEQ ID NOS: 6191, 6193, 6195, and 6197, respectively, or SEQ ID NOS: 6271, 6273, 6275, and 6277, respectively, or any of (iii-1) SEQ ID NOS: 6011, 6013, 6015, and 6017, respectively; (iii-2) SEQ ID NOS: 6021, 6023, 6025, and 6027, respectively; (iii-3) SEQ ID NOS: 6031, 6033, 6035, and 6037, respectively; (iii-4) SEQ ID NOS: 6041, 6043, 6045, and 6047, respectively; (iii-5) SEQ ID NOS: 6051, 6053, 6055, and 6057, respectively; (iii-6) SEQ ID NOS: 6061, 6063, 6065, and 6067, respectively; (iii-7) SEQ ID NOS: 6071, 6073, 6075, and 6077, 415respectively; (iii-8) SEQ ID NOS: 6081, 6083, 6085, and 6087, respectively; (iii-9) SEQ ID NOS: 6091, 6093, 6095, and 6097, respectively; (iii-10) SEQ ID NOS: 6101, 6103, 6105, and 6107, respectively; (iii-11) SEQ ID NOS: 6111, 6113, 6115, and 6117, respectively; (iii-12) SEQ ID NOS: 6121, 6123, 6125, and 6127, respectively; (iii-13) SEQ ID NOS: 6131, 6133, 6135, and 6137, respectively; (iii-14) SEQ ID NOS: 6141, 6143, 6145, and 6147, respectively; (iii-15) SEQ ID NOS: 6151, 6153, 6155, and 6157, respectively; (iii-16) SEQ ID NOS: 6161, 6163, 6165, and 6167, respectively; (iii-17) SEQ ID NOS: 6171, 6173, 6175, and 6177, respectively; (iii-18) SEQ ID NOS: 6181, 6183, 6185, and 6187, respectively; (iii-19) SEQ ID NOS: 6191, 6193, 6195, and 6197, respectively; (iii-20) SEQ ID NOS: 6201, 6203, 6205, and 6207, respectively; (iii-21) SEQ ID NOS: 6211, 6213, 6215, and 6217, respectively; (iii-22) SEQ ID NOS: 6221, 6223, 6225, and 6227, respectively; (iii-23) SEQ ID NOS: 6231, 6233, 6235, and 6237, respectively; (iii-24) SEQ ID NOS: 6241, 6243, 6245, and 6247, respectively; (iii-25) SEQ ID NOS: 6251, 6253, 6255, and 6257, respectively; (iii-26) SEQ ID NOS: 6261, 6263, 6265, and 6267, respectively; (iii-27) SEQ ID NOS: 6271, 6273, 6275, and 6277, respectively; (iii-28) SEQ ID NOS: 6281, 6283, 6285, and 6287, respectively; (iii-29) SEQ ID NOS: 6291, 6293, 6295, and 6297, respectively; (iii-30) SEQ ID NOS: 6301, 6303, 6305, and 6307, respectively; (iii-31) SEQ ID NOS: 6311, 6313, 6315, and 6317, respectively; (iii-32) SEQ ID NOS: 6321, 6323, 6325, and 6327, respectively; (iii-33) SEQ ID NOS: 6331, 6333, 6335, and 6337, respectively; (iii-34) SEQ ID NOS: 6341, 6343, 6345, and 6347, respectively; (iii-35) SEQ ID NOS: 6351, 6353, 6355, and 6357, respectively; (iii-36) SEQ ID NOS: 6361, 6363, 6365, and 6367, respectively; (iii-37) SEQ ID NOS: 6371, 6373, 6375, and 6377, respectively; (iii-38) SEQ ID NOS: 6381, 6383, 6385, and 6387, respectively; (iii-39) SEQ ID NOS: 6391, 6393, 6395, and 6397, respectively; (iii-40) SEQ ID NOS: 6401, 6403, 6405, and 6407, respectively; (iii-41) SEQ ID NOS: 6411, 6413, 6415, and 6417, 416respectively; (iii-42) SEQ ID NOS: 6421, 6423, 6425, and 6427, respectively; (iii-43) SEQ ID NOS: 6431, 6433, 6435, and 6437, respectively; (iii-44) SEQ ID NOS: 6441, 6443, 6445, and 6447, respectively; (iii-45) SEQ ID NOS: 6451, 6453, 6455, and 6457, respectively; (iii-46) SEQ ID NOS: 6461, 6463, 6465, and 6467, respectively; (iii-47) SEQ ID NOS: 6471, 6473, 6475, and 6477, respectively; or (iii-48) SEQ ID NOS: 6481, 6483, 6485, and 6487, respectively; SEQ ID NOS: 7011, 7013, 7015, and 7017, respectively, SEQ ID NOS: 7061, 7063, 7065, and 7067, respectively, SEQ ID NOS: 7131, 7133, 7135, and 7137, respectively, SEQ ID NOS: 7161, 7163, 7165, and 7167, respectively, or any of (iv-1) SEQ ID NOS: 7011, 7013, 7015, and 7017, respectively; (iv-2) SEQ ID NOS: 7021, 7023, 7025, and 7027, respectively; (iv-3) SEQ ID NOS: 7031, 7033, 7035, and 7037, respectively; (iv-4) SEQ ID NOS: 7041, 7043, 7045, and 7047, respectively; (iv-5) SEQ ID NOS: 7051, 7053, 7055, and 7057, respectively; (iv-6) SEQ ID NOS: 7061, 7063, 7065, and 7067, respectively; (iv-7) SEQ ID NOS: 7071, 7073, 7075, and 7077, respectively; (iv-8) SEQ ID NOS: 7081, 7083, 7085, and 7087, respectively; (iv-9) SEQ ID NOS: 7091, 7093, 7095, and 7097, respectively; (iv-10) SEQ ID NOS: 7101, 7103, 7105, and 7107, respectively; (iv-11) SEQ ID NOS: 7111, 7113, 7115, and 7117, respectively; (iv-12) SEQ ID NOS: 7121, 7123, 7125, and 7127, respectively; (iv-13) SEQ ID NOS: 7131, 7133, 7135, and 7137, respectively; (iv-14) SEQ ID NOS: 7141, 7143, 7145, and 7147, respectively; (iv-15) SEQ ID NOS: 7151, 7153, 7155, and 7157, respectively; (iv-16) SEQ ID NOS: 7161, 7163, 7165, and 7167, respectively; (iv-17) SEQ ID NOS: 7171, 7173, 7175, and 7177, respectively; (iv-18) SEQ ID NOS: 7181, 7183, 7185, and 7187, respectively; (iv-19) SEQ ID NOS: 7191, 7193, 7195, and 7197, respectively; (iv-20) SEQ ID NOS: 7201, 7203, 7205, and 7207, respectively; (iv-21) SEQ ID NOS: 7211, 7213, 7215, and 7217, respectively; (iv-22) SEQ ID NOS: 7221, 7223, 7225, and 7227, 417respectively; (iv-23) SEQ ID NOS: 7231, 7233, 7235, and 7237, respectively; (iv-24) SEQ ID NOS: 7241, 7243, 7245, and 7247, respectively; (iv-25) SEQ ID NOS: 7251, 7253, 7255, and 7257, respectively; (iv-26) SEQ ID NOS: 7261, 7263, 7265, and 7267, respectively; (iv-27) SEQ ID NOS: 7271, 7273, 7275, and 7277, respectively; (iv-28) SEQ ID NOS: 7281, 7283, 7285, and 7287, respectively; or (iv-29) SEQ ID NOS: 7291, 7293, 7295, and 7297, respectively; SEQ ID NOS: 8031, 8033, 8035, and 8037, respectively, or SEQ ID NOS: 8291, 8293, 8295, and 8297, respectively, or any of (v-1) SEQ ID NOS: 8011, 8013, 8015, and 8017, respectively; (v-2) SEQ ID NOS: 8021, 8023, 8025, and 8027, respectively; (v-3) SEQ ID NOS: 8031, 8033, 8035, and 8037, respectively; (v-4) SEQ ID NOS: 8041, 8043, 8045, and 8047, respectively; (v-5) SEQ ID NOS: 8051, 8053, 8055, and 8057, respectively; (v-6) SEQ ID NOS: 8061, 8063, 8065, and 8067, respectively; (v-7) SEQ ID NOS: 8071, 8073, 8075, and 8077, respectively; (v-8) SEQ ID NOS: 8081, 8083, 8085, and 8087, respectively; (v-9) SEQ ID NOS: 8091, 8093, 8095, and 8097, respectively; (v-10) SEQ ID NOS: 8101, 8103, 8105, and 8107, respectively; (v-11) SEQ ID NOS: 8111, 8113, 8115, and 8117, respectively; (v-12) SEQ ID NOS: 8121, 8123, 8125, and 8127, respectively; (v-13) SEQ ID NOS: 8131, 8133, 8135, and 8137, respectively; (v-14) SEQ ID NOS: 8141, 8143, 8145, and 8147, respectively; (v-15) SEQ ID NOS: 8151, 8153, 8155, and 8157, respectively; (v-16) SEQ ID NOS: 8161, 8163, 8165, and 8167, respectively; (v-17) SEQ ID NOS: 8171, 8173, 8175, and 8177, respectively; (v-18) SEQ ID NOS: 8181, 8183, 8185, and 8187, respectively; (v-19) SEQ ID NOS: 8191, 8193, 8195, and 8197, respectively; (v-20) SEQ ID NOS: 8201, 8203, 8205, and 8207, respectively; (v-21) SEQ ID NOS: 8211, 8213, 8215, and 8217, respectively; (v-22) SEQ ID NOS: 8221, 8223, 8225, and 8227, respectively; (v-23) SEQ ID NOS: 8231, 8233, 8235, and 8237, respectively; (v-24) SEQ ID NOS: 8241, 8243, 8245, and 8247, 418respectively; (v-25) SEQ ID NOS: 8251, 8253, 8255, and 8257, respectively; (v-26) SEQ ID NOS: 8261, 8263, 8265, and 8267, respectively; (v-27) SEQ ID NOS: 8271, 8273, 8275, and 8277, respectively; (v-28) SEQ ID NOS: 8281, 8283, 8285, and 8287, respectively; (v-29) SEQ ID NOS: 8291, 8293, 8295, and 8297, respectively; (v-30) SEQ ID NOS: 8301, 8303, 8305, and 8307, respectively; (v-31) SEQ ID NOS: 8311, 8313, 8315, and 8317, respectively; or (v-32) SEQ ID NOS: 8321, 8323, 8325, and 8327, respectively; SEQ ID NOS: 9031, 9033, 9035, and 9037, respectively, or SEQ ID NOS: 9121, 9123, 9125, and 9127, respectively, or any of (vi-1) SEQ ID NOS: 9011, 9013, 9015, and 9017, respectively; (vi-2) SEQ ID NOS: 9021, 9023, 9025, and 9027, respectively; (vi-3) SEQ ID NOS: 9031, 9033, 9035, and 9037, respectively; (vi-4) SEQ ID NOS: 9041, 9043, 9045, and 9047, respectively; (vi-5) SEQ ID NOS: 9051, 9053, 9055, and 9057, respectively; (vi-6) SEQ ID NOS: 9061, 9063, 9065, and 9067, respectively; (vi-7) SEQ ID NOS: 9071, 9073, 9075, and 9077, respectively; (vi-8) SEQ ID NOS: 9081, 9083, 9085, and 9087, respectively; (vi-9) SEQ ID NOS: 9091, 9093, 9095, and 9097, respectively; (vi-10) SEQ ID NOS: 9101, 9103, 9105, and 9107, respectively; (vi-11) SEQ ID NOS: 9111, 9113, 9115, and 9117, respectively; (vi-12) SEQ ID NOS: 9121, 9123, 9125, and 9127, respectively; (vi-13) SEQ ID NOS: 9131, 9133, 9135, and 9137, respectively; (vi-14) SEQ ID NOS: 9141, 9143, 9145, and 9147, respectively; (vi-15) SEQ ID NOS: 9151, 9153, 9155, and 9157, respectively; (vi-16) SEQ ID NOS: 9161, 9163, 9165, and 9167, respectively; (vi-17) SEQ ID NOS: 9171, 9173, 9175, and 9177, respectively; (vi-18) SEQ ID NOS: 9181, 9183, 9185, and 9187, respectively; (vi-19) SEQ ID NOS: 9191, 9193, 9195, and 9197, respectively; (vi-20) SEQ ID NOS: 9201, 9203, 9205, and 9207, respectively; (vi-21) SEQ ID NOS: 9211, 9213, 9215, and 9217, respectively; (vi-22) SEQ ID NOS: 9221, 9223, 9225, and 9227, respectively; (vi-23) SEQ ID NOS: 9231, 9233, 9235, and 9237, 419respectively; (vi-24) SEQ ID NOS: 9241, 9243, 9245, and 9247, respectively; (vi-25) SEQ ID NOS: 9251, 9253, 9255, and 9257, respectively; (vi-26) SEQ ID NOS: 9261, 9263, 9265, and 9267, respectively; (vi-27) SEQ ID NOS: 9271, 9273, 9275, and 9277, respectively; or (vi-28) SEQ ID NOS: 9281, 9283, 9285, and 9287, respectively; (2) (i) SEQ ID NOS: 111, 113, 115, and 117, respectively; (ii) SEQ ID NOS: 211, 213, 215, and 217, respectively; (iii) SEQ ID NOS: 311, 313, 315, and 317, respectively; (iv) SEQ ID NOS: 411, 413, 415, and 417, respectively; (v) SEQ ID NOS: 511, 513, 515, and 517, respectively; (vi) SEQ ID NOS: 611, 613, 615, and 617, respectively; (vii) SEQ ID NOS: 711, 713, 715, and 717, respectively; (viii) SEQ ID NOS: 811, 813, 815, and 817, respectively; (ix) SEQ ID NOS: 911, 913, 915, and 917, respectively; (x) SEQ ID NOS: 1011, 1013, 1015, and 1017, respectively; (xi) SEQ ID NOS: 1111, 1113, 1115, and 1117, respectively; (xii) SEQ ID NOS: 1211, 1213, 1215, and 1217, respectively; (xiii) SEQ ID NOS: 1311, 1313, 1315, and 1317, respectively; (xiv) SEQ ID NOS: 1411, 1413, 1415, and 1417, respectively; (xv) SEQ ID NOS: 1511, 1513, 1515, and 1517, respectively; (xvi) SEQ ID NOS: 1611, 1613, 1615, and 1617, respectively; (xvii) SEQ ID NOS: 1711, 1713, 1715, and 1717, respectively; (xviii) SEQ ID NOS: 1811, 1813, 1815, and 1817, respectively; (xix) SEQ ID NOS: 1911, 1913, 1915, and 1917, respectively; (xx) SEQ ID NOS: 2011, 2013, 2015, and 2017, respectively; (xxi) SEQ ID NOS: 2111, 2113, 2115, and 2117, respectively; (xxii) SEQ ID NOS: 2211, 2213, 2215, and 2217, respectively; (xxiii) SEQ ID NOS: 2311, 2313, 2315, and 2317, respectively; (xxiv) SEQ ID NOS: 2411, 2413, 2415, and 2417, respectively; (xxv) SEQ ID NOS: 2511, 2513, 2515, and 2517, respectively; (xxvi) SEQ ID NOS: 2611, 2613, 2615, and 2617, respectively; (xxvii) SEQ ID NOS: 2711, 2713, 2715, and 2717, respectively; (xxviii) SEQ ID NOS: 2811, 2813, 2815, and 2817, respectively; (xxix) SEQ ID NOS: 2911, 2913, 2915, and 2917, respectively; or (xxx) SEQ ID NOS: 3011, 3013, 3015, and 3017, respectively, or (2-a) SEQ ID NOS: 3111, 3113, 3115, and 3117, 420respectively, (2-b) SEQ ID NOS: 3211, 3213, 3215, and 3217, respectively, or (2-c) SEQ ID NOS: 3311, 3313, 3315, and 3317, respectively, except that the VH-1 comprises one or more of said one or more amino acid modifications,; (3) (xxxi) SEQ ID NOS: 10111, 10113, 10115, and 10117, respectively; (xxxii) SEQ ID NOS: 10211, 10213, 10215, and 10217, respectively; (xxxiii) SEQ ID NOS: 10311, 10313, 10315, and 10317, respectively; (xxxiv) SEQ ID NOS: 10411, 10413, 10415, and 10417, respectively; (xxxv) SEQ ID NOS: 10511, 10513, 10515, and 10517, respectively; (xxxvi) SEQ ID NOS: 10611, 10613, 10615, and 10617, respectively; (xxxvii) SEQ ID NOS: 10711, 10713, 10715, and 10717, respectively; (xxxviii) SEQ ID NOS: 10811, 10813, 10815, and 10817, respectively; (xxxix) SEQ ID NOS: 10911, 10913, 10915, and 10917, respectively; (xl) SEQ ID NOS: 11011, 11013, 11015, and 11017, respectively; (xli) SEQ ID NOS: 11111, 11113, 11115, and 11117, respectively; (xlii) SEQ ID NOS: 11211, 11213, 11215, and 11217, respectively; (xliii) SEQ ID NOS: 11311, 11313, 11315, and 11317, respectively; (xliv) SEQ ID NOS: 11411, 11413, 11415, and 11417, respectively; (xlv) SEQ ID NOS: 11511, 11513, 11515, and 11517, respectively; (xlvi) SEQ ID NOS: 11611, 11613, 11615, and 11617, respectively; (xlvii) SEQ ID NOS: 11711, 11713, 11715, and 11717, respectively; or (xlviii) SEQ ID NOS: 11811, 11813, 11815, and 11817, respectively, except that the VH-1 comprises one or more of said one or more amino acid modifications, optionally wherein the VH-1 comprises one or more of F or Y at position 37, E at position 44, and / or R at position 45, wherein the position is according to Kabat or Martin numbering.

8. The first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-7, which comprises: (a) a heavy chain-only antibody (HCAb) format, a nanobody-Fc format, a nanobody-CH format, a single chain nanobody-CH format, a camel Ig format, and / or an IgNAR format, or a single-chain variant of any of the foregoing; 421(b) a single domain antibody (sdAb) format, a nanobody format, a tandem nanobody format; and / or (c) a format depicted in any of FIGS.1A, 1C (top or second from top), and 1D (top left, bottom left, top right or second top on the right).

9. The first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-8, which comprises or consists of: (a) a HCAb comprising the VH-1, a nanobody-Fc comprising the VH-1, a nanobody-CH comprising the VH-1, a camel Ig comprising the VH-1, an IgNAR comprising the VH-1, and / or a single-chain variant of any of the foregoing; (b) a sdAb comprising the VH-1; a nanobody comprising the VH-1; and / or a tandem nanobody comprising the VH-1; and / or (c) the antibody structure depicted in any of FIGS.1A, 1C (top or second from top), and 1D (top left, bottom left, top right or second top on the right) comprising the VH- 1.

10. The first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-7, which further comprises a first light chain variable domain (VL-1) comprising: (a) a first light chain CDR1 (CDRL1-1); (b) a first light chain CDR2 (CDRH2-1); and (c) a first heavy chain CDR3 (CDRH3-1); optionally wherein the first anti-human CD3 antibody or antigen-binding antibody fragment comprises: (a) an immunoglobulin (Ig) format, optionally an IgG, IgA, IgE, IgD, or IgM format, further optionally an IgG1, IgG2, IgG3, or IgG4 format, or a half antibody variant of any of the foregoing; (b) an antibody fragment antigen-binding region (Fab) format, a Fab’ format, a F(ab’)2 format, a F(ab’)3format, and / or a variable fragment (Fv) format; (c) a single chain fragment variable region (scFv) format, a tandem scFv format, a diabody format, a triabody format, a tetrabody format, a scFv-Fc format, a scFv-CH 422format, a minibody format, a scFv-zipper format, a diabody-Fc format, a diabody-CH format, a half antibody variant of any of the foregoing, and / or a single chain Fab (scFab) format; and / or (d) a format depicted in any of FIGS.1B, 1C (third from the top or the bottom), and 1D (top center, bottom center, third from the top on the right, or the right bottom).

11. The first anti-human CD3 antibody or antigen-binding antibody fragment of claim 10, which comprises or consists of: (a) a heavy chain comprising the VH-1 and a light chain comprising the VL-1, optionally wherein the first anti-human CD3 antibody or antigen-binding antibody fragment: (a-1) consists of said heavy and light chains; (a-2) comprises or consists of an Ig molecule comprising two said heavy chains and two said light chains, or a multimer of said Ig molecule; and / or (a-3) comprises or consists of an IgG, IgA, IgE, IgD, or IgM, optionally an IgG1, IgG2, IgG3, or IgG4; and / or (b) a Fab comprising the VH-1 and the VL-1, a Fab’ comprising the VH-1 and the VL-1, a F(ab’)2comprising the VH-1 and the VL-1, a F(ab’)3comprising the VH-1 and the VL-1, and / or a Fv comprising the VH-1 and the VL-1; and / or (c) a scFv comprising the VH-1 and the VL-1, a tandem scFv comprising the VH-1 and the VL-1, a diabody comprising the VH-1 and the VL-1, a triabody comprising the VH-1 and the VL-1, a tetrabody comprising the VH-1 and the VL-1, a scFv-Fc comprising the VH-1 and the VL-1, a scFv-CH comprising the VH-1 and the VL-1, a minibody comprising the VH-1 and the VL-1, a scFv-zipper comprising the VH-1 and the VL-1, a diabody-Fc comprising the VH-1 and the VL-1, a diabody-CH comprising the VH-1 and the VL-1, and / or a scFab comprising the VH-1 and the VL-1; and / or (d) an antibody structure depicted in any of FIGS. 1B, 1C (third from the top or the bottom), and 1D (top center, bottom center, third from the top on the right, or the right bottom) comprising the VH-1 and the VL-1.

12. The first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-11, which comprises one or more of the following features: 423(a) (i) binds to cynomolgus CD3 and / or mouse CD3, (ii) does not bind to cynomolgus CD3, and / or (iii) does not bind to mouse CD3; (b) binds to human CD3 with a KDof < about 1 μM, < about 500 nM, < about 200 nM, < about 100 nM, < about 50 nM, < about 20 nM, < about 10 nM, < about 5 nM, < about 2 nM, < about 1 nM, < about 500 pM, about 1 μM, about 500 nM, about 200 nM, about 100 nM, about 50 nM, about 20 nM, about 10 nM, about 5 nM, about 2 nM, about 1 nM, about 500 pM, about 200 pM, between about 100 nM and 1 nM, between about 50 nM and 1 nM, between about 20 nM and 1 nM, between about 10 nM and 1 nM, between about 5 nM and 1 nM, between about 2 nM and 1 nM, between about 10 nM and 500 pM, between about 5 nM and 500 pM, between about 2 nM and 500 pM, between about 1nM and 500 pM, between about 1 nM and 200 pM, or between about 500 pM and about 200 pM, at a physiological pH or at pH 7.4, optionally as measured by surface plasmon resonance (SPR) or bio-layer interferometry (BLI), further optionally as performed in Example 3, 14, 19, 25, or 28; (c) binds to human CD3 with a KD of < about 1 μM, < about 500 nM, < about 200 nM, < about 100 nM, < about 50 nM, < about 20 nM, < about 10 nM, < about 5 nM, < about 2 nM, < about 1 nM, about 1 μM, about 500 nM, about 200 nM, about 100 nM, about 50 nM, about 20 nM, about 10 nM, about 5 nM, about 2 nM, or about 1 nM, at an acidic pH or at pH 6.0, optionally as measured by BLI, further optionally as performed in Example 3, 14, 19, 25, or 28; (d) binds to human CD3 with a lower KDat an acidic pH or at pH 6.0 compared to at a physiological pH or at pH 7.4, optionally by or at least by about 1.5-fold, about 2- fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 12-fold, about 15-fold, about 20-fold, about 25- fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 600-fold, about 700-fold, about 800-fold, about 900-fold, or about 1000-fold, optionally as measured by SPR or BLI, further optionally as performed in Example 3, 14, 19, 25, or 28; (e) binds to human CD3 at an acidic pH or at pH 6.0 but does not bind to human CD3 at a physiological pH or at pH 7.4, optionally as measured by SPR or BLI, further optionally as performed in Example 3, 14, 19, 25, or 28; 424(f) does not bind to mouse or murine CD3 or binds to mouse or murine CD3 with a KDof > about 10 nM, > about 20 nM, > about 50 nM, > about 100 nM, > about 200 nM, > about 500 nM, > about 1 μM, about 10 nM, about 20 nM, about 50 nM, about 100 nM, about 200 nM, about 500 nM, or about 1 μM, optionally as measured by SPR or BLI, further optionally as performed in Example 3, 14, 19, 25, or 28; (g) does not bind to human CD3 monomer or binds to human CD3 monomer with a KDof > about 1 nM, > about 10 nM, > about 20 nM, > about 50 nM, > about 100 nM, > about 200 nM, > about 500 nM, > about 1 μM, about 1 nM, about 10 nM, about 20 nM, about 50 nM, about 100 nM, about 200 nM, about 500 nM, or about 1 μM, optionally as measured by SPR or BLI, further optionally as performed in Example 3, 14, 19, 25, or 28; (h) competes with CTL-70330 (ADI-70330 in WO2023044402), CTL-96829 (UCHT1 IgG), CTL-62223 (the anti-CD3 arm of mosunetuzumab), or does not compete with any of CTL-70330, CTL-96829, or CTL-62223, optionally as measured by SPR or BLI, further optionally as performed in Example 4; (i) binds to human CD3 expressing cells, optionally Jurkat cells, cynomolgus HSC-F cells, and / or human CD3-CHO cells, more efficiently compared to one or more of CTL-70330, CTL-96829, or CTL-62223, optionally as measured by flow cytometry, further optionally based on median or median fluorescence intensity and / or normalized cell binding (NCB) values, yet further optionally as performed in Example 5; (j) displays a polyspecificity reagent (PSR) score of: score < 0.1 (clean); 0.10 ≤ score < 0.33 (low), or 0.33 ≤ score < 0.66 (medium), or 0.00 as measured by an PSR assay, optionally as performed in Example 6; (k) displays a hydrophobic interaction chromatography (HIC) retention time (RT) of: RT < 9.5 minutes, RT < 10.0 minutes, or RT < 10.5 minutes (clean or low), or 10.5 minutes ≤ RT < 11.5 minutes (medium), as measured by HIC, optionally as performed in Examples; (l) displays a melting temperature (Tm) of < about 45 ℃, < about 50 ℃, < about 55 ℃, < about 60 ℃, < about 65 ℃, < about 70 ℃, < about 75 ℃, < about 80 ℃, < about 85 ℃, > about 45 ℃, > about 50 ℃, > about 55 ℃, > about 60 ℃, > about 65 ℃, > about 70 ℃, > about 75 ℃, > about 80 ℃, > about 85 ℃, about 45 ℃, about 50 ℃, 425about 55 ℃, about 60 ℃, about 65 ℃, about 70 ℃, about 75 ℃, about 80 ℃, or about 85 ℃, optionally as measured by differential scanning fluorimetry (DSF), further optionally as performed in Examples; and / or (m) is capable of stimulating a T cell, as determined by at least one of: (m-1) increased expression of CD69, optionally as measured by flow cytometry, further optionally based on an increased mean fluorescence intensity (MFI), yet further optionally by about 5%, by about 10%, about 15%, by about 20%, about 25%, by about 30%, about 35%, by about 40%, about 45%, by about 50%, about 55%, by about 60%, about 65%, by about 70%, about 75%, by about 80%, about 85%, by about 90%, about 95%, by about 100%, by about 150%, by about 200%, by about 250%, by about 300%, by about 350%, by about 400%, by about 450%, or by 500%; (m-2) increased release of IL-2, optionally by or at least by about 1.5-fold, about 2- fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8- fold, about 9-fold, about 10-fold, about 12-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, or about 50-fold, optionally as measured by an immuno-assay, optionally Enzyme-linked immunosorbent assay (ELISA), optionally by about 5%, by about 10%, about 15%, by about 20%, about 25%, by about 30%, about 35%, by about 40%, about 45%, by about 50%, about 55%, by about 60%, about 65%, by about 70%, about 75%, by about 80%, about 85%, by about 90%, about 95%, by about 100%, by about 150%, by about 200%, by about 250%, by about 300%, by about 350%, by about 400%, by about 450%, or by 500%; or (m-3) increased transcriptional activation upon incubation of a T cell with the first anti-human CD3 antibody or antigen-binding antibody fragment and optionally with an anti-human cluster of differentiation 28 (CD28) antibody, optionally compared to incubation of the T cell with a control (e.g., not specific to CD3) antibody or antigen-binding antibody fragment or a reference anti-CD3 antibody, with or without an anti-CD28 antibody, further optionally as performed in Example 7; does not stimulate a T cell, as determined by at least one of: 426(m-4) no or minimal increase in expression of CD69, optionally as measured by flow cytometry, further optionally based on an increased mean fluorescence intensity (MFI), optionally wherein the minimal increase is by about 5% or below, by about 10%, about 15% or below, by about 20% or below, about 25% or below, by about 30% or below, about 35% or below, by about 40% or below, about 45% or below, by about 50% or below, about 55% or below, by about 60% or below, about 65% or below, by about 70% or below, about 75% or below, by about 80% or below, about 85% or below, by about 90% or below, about 95% or below, by about 100% or below, by about 150% or below, by about 200% or below, by about 250% or below, by about 300% or below, or by about 350% or below; (m-5) no or minimal increase in release of IL-2, optionally as measured by an immuno-assay, optionally Enzyme-linked immunosorbent assay (ELISA), optionally wherein the minimal increase is by about 1.05-fold or below, about 1.1- fold or below, about 1.15-fold or below, about 1.2-fold or below, about 1.5-fold or below, about 2-fold or below, about 3-fold or below, about 4-fold or below, about 5- fold or below, about 6-fold or below, or about 7-fold or below, by about 5% or below, by about 10% or below, about 15% or below, by about 20% or below, about 25% or below, by about 30% or below, about 35% or below, by about 40% or below, about 45% or below, by about 50% or below, about 55% or below, by about 60% or below, about 65% or below, by about 70% or below, about 75% or below, by about 80% or below, about 85% or below, by about 90% or below, about 95% or below, by about 100% or below, by about 150% or below, by about 200% or below, by about 250% or below, by about 300% or below, by about 350% or below, by about 400% or below, by about 450% or below, or by 500% or below; or (m-6) no or minimal increase in transcriptional activation upon incubation of a T cell with the first anti-human CD3 antibody or antigen-binding antibody fragment and optionally with an anti-human cluster of differentiation 28 (CD28) antibody, optionally compared to incubation of the T cell with a control (e.g., not specific to CD3) antibody or antigen-binding antibody fragment with or without an anti-CD28 antibody, further optionally as performed in Example 21; or reverses, inhibit, or suppress T cell or T cell activation, 427(m-7) reduced expression of CD69, optionally as measured by flow cytometry, further optionally based on an increased mean fluorescence intensity (MFI), yet further optionally by about 5%, by about 10%, about 15%, by about 20%, about 25%, by about 30%, about 35%, by about 40%, about 45%, by about 50%, about 55%, by about 60%, about 65%, by about 70%, about 75%, by about 80%, about 85%, by about 90%, about 95%, or by about 100%; (m-8) reduced release of IL-2, optionally as measured by an immuno-assay, optionally Enzyme-linked immunosorbent assay (ELISA), optionally by about 5%, by about 10%, about 15%, by about 20%, about 25%, by about 30%, about 35%, by about 40%, about 45%, by about 50%, about 55%, by about 60%, about 65%, by about 70%, about 75%, by about 80%, about 85%, by about 90%, about 95%, or by about 100%; or (m-9) reduced transcriptional activation upon incubation of a T cell with the first anti-human CD3 antibody or antigen-binding antibody fragment and optionally with an anti-human cluster of differentiation 28 (CD28) antibody, optionally compared to incubation of the T cell with a control (e.g., not specific to CD3) antibody or antigen-binding antibody fragment or a reference anti-CD3 antibody, with or without an anti-CD28 antibody, further optionally as performed in Example 21; 13. A multi-specific antibody, comprising: (1) a first antigen-binding region (ABR-1) that binds human CD3, wherein the ABR-1 comprises the first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-12; and (2) a second antigen-binding region (ABR-2) that binds a second antigen, optionally wherein the ABR-2 comprises: (2-i) a second heavy chain variable domain (VH-2) comprising a second heavy chain complementarity determining region (CDR) 1 (CDRH1-2), a second heavy chain CDR2 (CDRH2-2), and a second heavy chain CDR3 (CDRH3-2); and 428optionally a second light chain variable domain (VL-2) comprising a second light chain CDR1 (CDRL1-2), a second light chain CDR2 (CDRL2-2), and a second light chain CDR3 (CDRL3-2); or (2-ii) a TCR α-chain variable domain (Vα) and / or a TCR β-chain variable domain (Vβ), wherein the second antigen is optionally the same as or different from human CD3, optionally wherein the multi-specific antibody is bispecific, trispecific, or tetraspecific.

14. The multi-specific antibody of claim 13, wherein the second antigen is or comprises: (a) CD28, optionally human CD28; (b) a cancer antigen, optionally a tumor-specific antigen (TSA) or a tumor-associated antigen (TAA), optionally CD20; (c) CD3, optionally human CD3; (d) any one of the antigens selected from those listed in Table 2; (e) any one of the cancer antigens, optionally any one of the TSAs or any one of the TAAs, selected from those listed in Table 2; and / or (f) a molecule of interest presented on a major histocompatibility complex (MHC), optionally wherein: (i) the molecule of interest comprises a cancer antigen, optionally any one of the TSAs or any one of the TAAs optionally selected from those listed in Table 2, or a fragment thereof; and / or (ii) the MHC is a MHC class I molecule, optionally HLA-A, HLA-B, or HLA-C, further optionally HLA-A2; further optionally wherein the second antigen is or comprises gp100 presented on MHC class I, optionally HLA-A, further optionally HLA-A2.

15. The multi-specific antibody of claim 13 or 14, wherein: (1) the ABR-1 comprises a heavy chain comprising the VH-1, optionally wherein: 429(a) the ABR-1 consists of said heavy chain or further comprises a light chain comprising a VL-1; (b) the heavy chain comprises a heavy chain constant region, optionally comprising one or more heavy chain constant domains and / or a hinge, optionally wherein the one or more heavy chain constant domains and / or the hinge: (b-1) comprise one or more of CH3, CH2, and CH1, further optionally comprising CH2 and CH3 or comprising CH1, CH2, and CH3; and / or (b-2) is / are individually of an IgG, IgA, IgE, IgD, or IgM class, optionally an IgG1, IgG2, IgG3, or IgG4 subclass; (c) the ABR-1comprises or consists of a half antibody variant of a heavy chain- only antibody (HCAb); (d) the ABR-1 comprises or consists of a half antibody variant of an immunoglobulin (Ig) molecule, optionally of an IgG, IgE, or IgD; and / or (e) the ABR-1 comprises a structure described in FIG.1D, optionally the top left (boxed) structure or the bottom left structure thereof; and (2) the ABR-2 comprises a heavy chain comprising a / the VH-2 or comprises an α-chain comprising a / the Vα and / or a β-chain comprising a / the Vβ, optionally wherein the ABR- 2: (a) the ABR-2 consists of said heavy chain or further comprises a light chain comprising the VL-2 or consists of said α-chain and said β-chain; (b) said heavy chain comprises a heavy chain constant region, optionally comprising one or more heavy chain constant domains and / or a hinge, optionally wherein the one or more heavy chain constant domains and / or the hinge: (b-1) comprise one or more of CH3, CH2, and CH1, further optionally comprising CH2 and CH3 or comprising CH1, CH2, and CH3; and / or (b-2) is / are individually of an IgG, IgA, IgE, IgD, or IgM class, optionally an IgG1, IgG2, IgG3, or IgG4 subclass; or said α-chain comprises a α-chain constant domain (Cα) and / or said β-chain comprises a β-chain constant domain (Cβ), optionally wherein the α-chain comprises the Vα and the Cα in the direction from the N-terminus to the C- 430terminus and / or said β-chain comprises the Vβ and the Cβ in the direction from the N-terminus to the C-terminus; (c) the ABR-2 comprises or consists of a half antibody variant of a heavy chain- only antibody (HCAb); and / or (d) the ABR-2 comprises or consists of a half antibody variant of an immunoglobulin (Ig) molecule, optionally of an IgG, IgE, or IgD; and / or (e) the ABR-2 comprises a structure described in FIG.1D, optionally the bottom center structure, the top left (boxed) structure, the top center structure, or the bottom left structure thereof, optionally wherein: (1) the ABR-1 comprises the top left (boxed) structure of FIG.1D and the ABR-2 comprises the bottom center structure of FIG.1D; or the ABR-1 comprises the top right structure of FIG.1D and the ABR-2 comprises an α-chain comprises a / the Vα and a / the Cα optionally in the direction from the N- terminus to the C-terminus and a β-chain comprises a / the Vβ and a / the Cβ optionally in the direction from the N-terminus to the C-terminus; (2) the ABR-1 and the ABR-2 are associated with or linked to each other via one or more disulfide bonds or a linker, optionally a peptide linker, further optionally a flexible peptide linker; (3) the multi-specific antibody comprises the ABR-1 and the ABR-2 at 1:1, optionally one each; (4) the multi-specific antibody comprises a structure depicted in any one of FIG.2A, optionally the top left (boxed) structure, the bottom left structure, or the top right structure thereof, optionally wherein: (4-i) ABR-A and ABR-B of FIG.2A are the ABR-1 and the ABR-2, respectively; (4-ii) VH-A and VH-B of FIG.2A are the VH-1 and the VH-2, respectively; (4-iii) VL-A (if present) of FIG.2A is the VL-1 (if present); and / or (4-iv) VL-B (if present) of FIG.2A is the VL-2 (if present); or 431(5) the multi-specific antibody comprises a structure depicted in any one of FIG.2C, optionally the bottom left (solid box) structure or a variant thereof on the bottom, the top left structure (dashed box), or the top center or right structure thereof, optionally wherein:. (5-i) ABR-A and ABR-B of FIG.2C are the ABR-1 and the ABR-2, respectively; (5-ii) VH-A of FIG.2C is the VH-1; (5-iii) Vα-B of FIG.2C is the Vα of ARB-2; and / or (5-iv) Vβ-B of FIG.2C is the Vβ of ARB-2.

16. The multi-specific antibody of claim 13 or 14, wherein: (1) the ABR-1 comprises a sdAb comprising the VH-1 and / or a nanobody comprising the VH-1; and / or (2) the ABR-2 comprises: (a) a heavy chain comprising a / the VH-2 and a light chain comprising a / the VL-2, optionally wherein the ABR-2: (a-1) consists of said heavy and light chains; (a-2) comprises or consists of an Ig molecule comprising two said heavy chains and two said light chains, or a multimer of said Ig molecule; and / or (a-3) comprises or consists of an IgG, IgA, IgE, IgD, or IgM, optionally an IgG1, IgG2, IgG3, or IgG4; or an α-chain comprising a Vα and a β-chain comprising a Vβ; (b) a Fab comprising the VH-2 and the VL-2; or a pair of an α-chain comprising a / the Vα and an Cα and a β-chain comprising a / the Vβ and a Cβ, optionally wherein the α-chain comprises the Vα and the Cα in the direction from the N-terminus to the C-terminus and / or said β-chain comprises the Vβ and the Cβ in the direction from the N-terminus to the C-terminus; (c) a scFv comprising the VH-2 and the VL-2, optionally wherein the scFv comprises the VH-2, a linker, and the VL-2 in the direction from the N-terminus to the C- 432terminus or the VL-2, a linker, and the VH-2 in the direction from the N-terminus to the C-terminus; or a single chain comprising a / the Vα and a / the Vβ, optionally wherein the single chain comprises the Vα, a linker, and the Vβ in the direction from the N-terminus to the C-terminus or comprises the Vβ, a linker, and the Vα in the direction from the N-terminus to the C-terminus; and / or (e) a sdAb comprising the VH-2, optionally wherein: (1) the ABR-1 and the ABR-2 are associated with or linked to each other via a linker, optionally a peptide linker, further optionally a flexible peptide linker, or via one or more disulfide bonds; (2) the multi-specific antibody comprises the ABR-1 and the ABR-2 at 1:1, 2:1, 4:1, 6:1, or 8:1, optionally comprising one, two, three, four, five, six, seven, or eight ABR-1 and one or two ABR-2; (3) the multi-specific antibody comprises a structure depicted in any one of FIG.2B, optionally the top left structure thereof, optionally wherein: (3-i) ABR-A and ABR-B of FIG.2B are the ABR-1 and the ABR-2, respectively; (3-ii) VH-A and VH-B of FIG.2B are the VH-1 and the VH-2, respectively, or the VH-1 and the Vα, respectively; (3-iii) VL-A (if present) of FIG.2B is the VL-1 (if present); and / or (3-iv) VL-B (if present) of FIG.2B is the VL-2 (if present) or the Vβ (if present).

17. The multi-specific antibody of any one of claim 13-16, wherein: (1) the ABR-1 comprises: at least one Ig constant domain and / or hinge, optionally one or more of a heavy chain constant domain 1 (CH1), a hinge, a heavy chain constant domain 2 (CH2), a heavy chain constant domain 3 (CH3), a light chain constant domain (CL); a fragment crystallizable (Fc) region, and / or a TCR constant domain, optionally wherein: (a) the CH1, hinge, CH2, and / or the CH3 is / are individually of an IgG, IgA, IgE, IgD, or IgM class, optionally of an IgG1, IgG2, IgG3, and / or IgG4 subclass; 433(b) the CL is of a kappa isotype (CLκ) or a lambda isotype (CLλ); (c) the Fc region is of an IgG, IgA, IgE, IgD, or IgM class, optionally of an IgG1, IgG2, IgG3, and / or IgG4 subclass; and / or (d) the TCR constant domain is a Cα or a Cβ; (2) the ABR-2 comprises: at least one Ig constant domain and / or hinge, optionally one or more of a CH1, a hinge, a CH2, a CH3, a CL, a Fc region, and / or a TCR constant domain, optionally wherein: (a) the CH1, hinge, CH2, and / or the CH3 is / are individually of an IgG, IgA, IgE, IgD, or IgM class, optionally of an IgG1, IgG2, IgG3, and / or IgG4 subclass; (b) the CL is a CLκ or a CLλ; (c) the Fc region is of an IgG, IgA, IgE, IgD, or IgM class, optionally of an IgG1, IgG2, IgG3, and / or IgG4 subclass; and / or (d) the TCR constant domain is a Cα or a Cβ; (3) the multi-specific antibody comprises common light chains, and / or the VL-1 (if present) and the VL-2 (if present) have the same or essentially the same amino acid sequences; and / or (4) the multi-specific antibody comprises one or more of the following: (4-i) a heavy chain constant region (CH), optionally a CH1, which is engineered to promote pairing with a CLκ over a CLλ, optionally wherein the CH1 engineering comprises the incorporation of one of the variant CH1 domains described in WO2021067404; (4-ii) a CH, optionally a CH1, which is engineered to promote pairing with a CLλ over a CLκ, optionally wherein the CH1 engineering comprises the incorporation of one variant CH1 domains described in WO2021067404; and / or (4-iii) a CH, optionally a CH1, which is engineered to promote pairing with an engineered CL comprised in the multi-specific antibody over another CL, optionally wherein the combination of the CH engineering and the CL engineering comprises the incorporation of one of the variant CH1 and / or CL domains described in WO2022150787; and / or 434(4-iv) at least two CHs having different amino acid sequences, optionally at least two CH3s having different amino acid sequences, which are engineered to promote heteromeric paring between the two CHs over homomeric pairing, optionally wherein the CH3 engineering comprises the incorporation of one of the variant CH3 domains described in WO2022150785.

18. The multi-specific antibody of any one of claims 13-17, which binds monovalently, bivalently, trivalently, or tetravalently to: (a) CD28, optionally human CD28; (b) a cancer antigen, optionally a TSA or a TAA, optionally CD20; (c) CD3, optionally human CD3; (d) any one of the antigens selected from those listed in Table 2; (e) any one of the cancer antigens, optionally any one of the TSAs or any one of the TAAs, selected from those listed in Table 2; and / or (f) a molecule of interest presented on a major histocompatibility complex (MHC), optionally wherein: (i) the molecule of interest comprises a cancer antigen, optionally any one of the TSAs or any one of the TAAs optionally selected from those listed in Table 2, or a fragment thereof; and / or (ii) the MHC is a MHC class I molecule, optionally HLA-A, HLA-B, or HLA-C, further optionally HLA-A2; further optionally wherein the second antigen is or comprises gp100 presented on MHC class I, optionally HLA-A, further optionally HLA-A2.

19. A nucleic acid encoding the first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-12 or the multi-specific antibody of any one of claims 13- 18 or a portion thereof, optionally comprising: a VH-1-encoding nucleic acid having at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least 435about 99%, or 100% identity to any one of the VH-encoding sequences of Table 13D, 1D, or 24D; and optionally a VL-1-encoding nucleic acid.

20. A vector comprising the nucleic acid of claim 19, optionally wherein: (i) the vector is an expression vector; and / or (ii) the vector comprises a plasmid, a viral vector (optionally adenoviral, lentiviral, or retroviral), a lipid-based vector, a self-replicating RNA vector, a virus-like particle, a polymer-based vector, and / or a nanoparticle, optionally a lipid-based nanoparticle.

21. An isolated and / or recombinant host cell comprising the nucleic acid of claim 19 or the vector of claim 20, or a population of such cells, optionally wherein the isolated and / or recombinant host cell is: (i) non-mammalian, optionally bacterial, yeast, fungal, protozoa, plant, or insect, bacterial; or (ii) mammalian, optionally human, non-human primate, monkey, rabbit, rodent, hamster, rat, or mouse.

22. A composition comprising: (A) at least one of: the first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-12 or the multi-specific antibody of any one of claims 13-18; the nucleic acid of claim 19; the vector of claim 20; and / or the isolated and / or recombinant host cell of claim 21; (B) a pharmaceutically acceptable carrier / excipient, optionally further comprising an additional agent, optionally an adjuvant or a therapeutic agent.

23. A method of treating a disease, disorder, or condition in a subject, the method comprising administering to the subject an effective amount of at least one of: 436the first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-12 or the multi-specific antibody of any one of claims 13-18; the nucleic acid of claim 19; the vector of claim 20; the isolated and / or recombinant host cell of claim 21; and / or the composition of claim 22, optionally wherein: (a) the subject is (i) a mammal, optionally a human, a non-human primate, a monkey, a horse, a cow, sheep, a goat, a pig, a dog, a cat, a rabbit, a rodent, a hamster, a rat, or a mouse; or (ii) a non-mammalian vertebrate, optionally a bird, fish, an amphibian, or a reptile; and / or (b) the method further comprises administering to the subject an additional agent, optionally an adjuvant or a therapeutic agent.

24. The method of claim 23, wherein the disease, disorder, or a condition comprises cancer or a neoplastic condition, an autoimmune disease, a neurodegenerative disease, an infectious disease, an inflammatory disease, or another disease, optionally wherein: (i) the cancer is: (i-1) a solid cancer, optionally chosen from: one or more of mesothelioma, malignant pleural mesothelioma, non-small cell lung cancer, small cell lung cancer, squamous cell lung cancer, large cell lung cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, esophageal adenocarcinoma, breast cancer, glioblastoma, ovarian cancer, colorectal cancer, prostate cancer, cervical cancer, skin cancer, melanoma, renal cancer, liver cancer, brain cancer, thymoma, sarcoma, carcinoma, uterine cancer, kidney cancer, gastrointestinal cancer, urothelial cancer, pharynx cancer, head and neck cancer, rectal cancer, esophagus cancer, or bladder cancer, or a metastasis thereof; and / or (i-2) a liquid cancer, optionally chosen from: chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), multiple myeloma, acute lymphoid leukemia (ALL), Hodgkin lymphoma, B-cell acute lymphoid leukemia (BALL), T-cell acute 437lymphoid leukemia (TALL), small lymphocytic leukemia (SLL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma (DLBCL), DLBCL associated with chronic inflammation, chronic myeloid leukemia, myeloproliferative neoplasms, follicular lymphoma, pediatric follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma (extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue), Marginal zone lymphoma, myelodysplasia, myelodysplastic syndrome, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, splenic lymphoma / leukemia, splenic diffuse red pulp small B-cell lymphoma, hairy cell leukemia-variant, lymphoplasmacytic lymphoma, a heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, primary cutaneous follicle center lymphoma, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+large B-cell lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, primary effusion lymphoma, B-cell lymphoma, acute myeloid leukemia (AML), or unclassifiable lymphoma; (ii) the autoimmune or inflammatory disease is psoriasis, rheumatoid arthritis, autoimmune arthritis, type I diabetes, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, scleroderma, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, pemphigus vulgaris, Sjogren’s syndrome, Addison’s disease, Behcet’s disease, Schmidt syndrome, celiac disease, dermatomyositis, autoimmune vitiligo, Graves’ disease, Hashimoto thyroiditis, Kawasaki disease, pernicious anemia, autoimmune vasculitis, or fibrosis; (iii) the neurodegenerative disease is Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Friedreich ataxia, Lewy body disease, spinal muscular atrophy, motor neuron disease, multiple sclerosis, Batten disease, Creutzfeldt-Jakob disease; (iv) the infectious disease is a viral, bacterial, fungal, yeast, protozoan, prion or parasitic disease, optionally wherein (1) the viral disease is human immunodeficiency virus 438(HIV), hepatitis virus (optionally hepatitis A, B, or C virus), human papillomavirus (HPV), herpes simplex virus (HSV) (optionally HSV-1 or HSV-2), enterovirus, human cytomegalovirus, adenovirus, rhinovirus, Pox virus, Influenza virus, coronavirus (optionally MERS-CoV, SARS-CoV, or SARS-CoV-2, or common human coronavirus), norovirus, West Nile Virus, Zika virus, poliovirus, Ebola virus, or dengue virus (DENV) infection, (2) the bacterial disease is Salmonella, Escherichia coli, Mycobacterium tuberculosis, methicillin-resistant staphylococcus aureus (MRSA), Clostridium difficile, Streptococcus pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Helicobacter pylori, Neisseria gonorrhoeae, Vibrio vulnificus, and / or (3) the fungal disease is Aspergillosis, Candida, Candida auris, Cryptococcus neoformans, Pneumocystis jirovecii, Mucormycetes, Taloromyces, ringworm, Blastomyces, Coccidioides, Cryptococcus gattii, Histoplasma, Paracoccidioides, or Sporothrix infection.

25. A method of activating and / or depleting a CD3+ cell or preventing, suppressing, or reversing CD3+ cell activation, the method comprising contacting the CD3+ cell with the first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1- 12 or the multi-specific antibody of any one of claims 13-18, optionally wherein: (1) the CD3+ cell is a T cell or a cell of T cell lineage, optionally: (1-i) a T cell progenitor cell, a CD4+ T cell, a helper T cell, a regulatory T cell, a CD8+ T cell, a naïve T cell, an effector T cell, a memory T cell, a stem cell memory T (TSCM) cell, a central memory T (TCM) cell, an effector memory T (TEM) cell, a terminally differentiated effector memory T cell, a tumor-infiltrating lymphocyte (TIL), an immature T cell, a mature T cell, a cytotoxic T cell, a mucosa-associated invariant T (MAIT) cell, a TH1 cell, a TH2 cell, a TH3 cell, a TH17 cell, a TH9 cell, a TH22 cell, a follicular helper T cells, and a / b T cell, a g / d T cell, a Natural Killer T (NKT) cell, a cytokine-induced killer (CIK) cell, a lymphokine-activated killer (LAK) cell, a perforin-deficient cell, a granzyme-deficient cell, a B cell, a myeloid cell, a monocyte, a macrophage, or a dendritic cell; and / or (1-ii) a cancer cell of T cell lineage, optionally leukemia or lymphoma, further optionally non-Hodgkin lymphoma, or optionally T-lymphoblastic lymphoma (T- 439LBL) / T-lymphoblastic leukemia (T-ALL), peripheral T-cell lymphoma, T-cell prolymphocytic leukemia (T-PLL), optionally wherein: the T-lymphoblastic lymphoma / leukemia is acute lymphoblastic leukemia (ALL) and / or precursor T-lymphoblastic lymphoma; and / or the peripheral T-cell lymphoma is one or more of cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome, etc), adult T-cell leukemia / lymphoma, angioimmunoblastic T-cell lymphoma (AITL), extranodal natural killer / T-cell lymphoma, nasal type (ENKTL / NKTCL), enteropathy-associated intestinal T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T cell lymphoma (MEITL), anaplastic large cell lymphoma (ALCL) (e.g., primary cutaneous ALCL, systemic ALCL, breast implant-associated ALCL, etc), or peripheral T- cell lymphoma, not otherwise specified (PTCL, NOS); (2) the contacting occurs in vitro, ex vivo, or in vivo.

26. A method of directing a CD3+ cell to a target cell, the method comprising contacting a CD3+ cell and a target cell expressing the second antigen with the multi-specific antibody of any one of claims 13-18, optionally wherein: (1) the CD3+ cell is a T cell or a cell of T cell lineage, optionally a T cell progenitor cell, a CD4+ T cell, a helper T cell, a regulatory T cell, a CD8+ T cell, a naïve T cell, an effector T cell, a memory T cell, a stem cell memory T (TSCM) cell, a central memory T (TCM) cell, an effector memory T (TEM) cell, a terminally differentiated effector memory T cell, a tumor-infiltrating lymphocyte (TIL), an immature T cell, a mature T cell, a cytotoxic T cell, a mucosa-associated invariant T (MAIT) cell, a TH1 cell, a TH2 cell, a TH3 cell, a TH17 cell, a TH9 cell, a TH22 cell, a follicular helper T cells, and a / b T cell, a g / d T cell, a Natural Killer T (NKT) cell, a cytokine-induced killer (CIK) cell, a lymphokine-activated killer (LAK) cell, a perforin-deficient cell, a granzyme-deficient cell, a B cell, a myeloid cell, a monocyte, a macrophage, or a dendritic cell; and / or (2) the target cell is a cell associated with or involved in the pathogenesis or pathology of a disease, a disorder, or a condition optionally any of the disease, disorder, or condition listed in claim 24; (3) the second antigen is any of those listed in claim 14; 440(4) the contacting occurs in vitro, ex vivo, or in vivo; and / or (5) the method is a method for eliciting cytotoxicity to the target cell.

27. A method of manufacturing the first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-12 or the multi-specific antibody of any one of claims 13-18, comprising: (a) culturing cells comprising the nucleic acid of claim 19 in a condition that allows for expression of said antibody or antigen-binding antibody fragment or said multi-specific antibody, and (b) harvesting and purifying the antibody or antigen-binding antibody fragment or the multi-specific antibody from the cell culture from (a).

28. A method of manufacturing the isolated and / or recombinant host cell of claim 21 or a population of such cells, comprising introducing the nucleic acid of claim 19 and / or the vector of claim 20 into one or more cells, optionally wherein the introducing occurs in vitro, ex vivo, or in vivo.

29. The first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-12 or the multi-specific antibody of any one of claims 13-18, the nucleic acid of claim 19, the vector of claim 20, the isolated and / or recombinant host cell of claim 21 or a population of such cells, the composition of claim 22, for use in medicine and / or for use in treating a disease, disorder, or condition, optionally wherein the disease, disorder, or condition comprises any one or more of those according to claim 24.

30. Use of a first anti-human CD3 antibody or antigen-binding antibody fragment of any one of claims 1-12 or the multi-specific antibody of any one of claims 13-18, the nucleic acid of claim 19, the vector of claim 20, the isolated and / or recombinant host cell of claim 21 or a population of such cells, the composition of claim 22, or for use according to any one of the methods of claims 23-28 or for the manufacture of a medicament for treatment of a disease, disorder, or condition, optionally wherein the disease, disorder, or condition comprises any one or more of those according to claim 24. 441

Citation Information

Patent Citations

  • Anti-CD3 antibodies and methods of use thereof

    US20180194842A1

  • Binding moiety for conditional activation of immunoglobulin molecules

    US20210292421A1

  • Anti-CD3 antibodies

    WO2023044402A1

  • Anti-CD3 monoclonal antibodies and therapeutic constructs

    WO2023056556A1