Use of CD79B Antibodies for Autoimmune Therapeutic Applications

Abstract

The present disclosure provides antigen binding domains that bind to Cluster of Differentiation 79B protein (CD79B), including antigen binding domains that bind CD79b, polynucleotides encoding them, vectors, host cells, and methods of making and using them.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 160,127, filed March 12, 2021, and U.S. Provisional Application No. 63 / 252,910, filed October 6, 2021, each of which is incorporated by reference in its entirety herein.

[0002] (Technical field) The present disclosure provides antigen binding domains that bind to Cluster of Differentiation 79B protein (CD79B), including antigen binding domains that bind CD79b, polynucleotides encoding them, vectors, host cells, and methods of making and using them. [Background technology]

[0003] The prevalence of autoimmune diseases is estimated to be 3-5% of the general population, and B cell dysregulation, autoreactive B cells, and the presence of autoantibodies are common features of many autoimmune diseases (Wang et al., 2015, J Intern Med 2015;278:369-395).

[0004] B cells (or B lymphocytes) are the central component of adaptive immunity, responding to several different pathogens by producing antibodies, acting as antigen-presenting cells, secreting cytokines, and developing into memory B cells after activation (Packard and Cambier, 2013, F1000 Prime Rep, 5:40). B cells circulate in the blood and lymphatic system. In lymphoid organs, B cells encounter their cognate antigen and, with additional signals from T helper cells, can differentiate into effector plasma cells. These cells secrete specific antibodies that circulate in the blood to target and eliminate antigens or pathogens (Puri et al., 2013, Int Rev Immunol, 32(4):397-427).

[0005] In healthy individuals, immune tolerance prevents the immune system from recognizing self-antigens, thereby limiting the targeting and destruction of healthy cells and tissues by B cells, T cells, and myeloid cells. However, autoimmune diseases are characterized by a breakdown in tolerance, which allows immune cells to recognize and react to self-antigens. In such cases, B cells recognize and produce antibodies against self-antigens ("autoantibodies"), and these antibodies can then target cells and tissues for destruction by other components of the immune system, such as complement, cytotoxic T cells, and myeloid cells.

[0006] To detect antigens, either pathogen-derived or self-antigens, B cells express a multicomponent receptor, the cell surface receptor (BCR), composed of transmembrane immunoglobulin molecules (mIg) and disulfide-linked heterodimers of CD79a (Igα) and CD79b (Igβ) (Chu et al., 2001, Appl Immunohistochem Mol Morphol, Jun;9(2):97-106). CD79b is selectively expressed within the B cell lineage and across many differentiation states of B cells. Activation of the BCR leads to multiple immune activation outcomes, including B cell differentiation, production of antibodies and autoantibodies, cytokine production, and antigen presentation to T cells. Summary of the Invention

[0007] In one aspect, the disclosure provides an isolated protein comprising an antigen-binding domain that binds to Cluster of Differentiation 79B protein (CD79b). In one embodiment, the antigen-binding domain that binds to CD79b comprises at least one complementarity determining region (CDR) selected from the group consisting of heavy chain complementarity determining region (HCDR)1, HCDR2, HCDR3, light chain complementarity determining region (LCDR)1, LCDR2, and LCDR3.

[0008] In one embodiment, HCDR1 is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, and SEQ ID NO:131; HCDR2 is selected from the group consisting of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, and SEQ ID NO:132; and HCDR3 is selected from the group consisting of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, and SEQ ID NO:133. and LCDR1 is selected from the group consisting of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, and SEQ ID NO:134; LCDR2 is selected from the group consisting of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, and SEQ ID NO:135; and LCDR3 is selected from the group consisting of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, and SEQ ID NO:136.

[0009] In one embodiment, an antigen binding domain that binds to CD79b comprises HCDR1, HCDR2 and HCDR3. (a) HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; (b) HCDR1 of SEQ ID NO: 11, HCDR2 of SEQ ID NO: 12, and HCDR3 of SEQ ID NO: 13; (c) HCDR1 of SEQ ID NO: 21, HCDR2 of SEQ ID NO: 22, and HCDR3 of SEQ ID NO: 23; (d) HCDR1 of SEQ ID NO: 31, HCDR2 of SEQ ID NO: 32, and HCDR3 of SEQ ID NO: 33; (e) HCDR1 of SEQ ID NO: 41, HCDR2 of SEQ ID NO: 42, and HCDR3 of SEQ ID NO: 43; (f) HCDR1 of SEQ ID NO: 51, HCDR2 of SEQ ID NO: 52, and HCDR3 of SEQ ID NO: 53; (g) HCDR1 of SEQ ID NO: 61, HCDR2 of SEQ ID NO: 62, and HCDR3 of SEQ ID NO: 63; (h) HCDR1 of SEQ ID NO: 71, HCDR2 of SEQ ID NO: 72, and HCDR3 of SEQ ID NO: 73; (i) HCDR1 of SEQ ID NO: 81, HCDR2 of SEQ ID NO: 82, and HCDR3 of SEQ ID NO: 83; (j) HCDR1 of SEQ ID NO: 91, HCDR2 of SEQ ID NO: 92, and HCDR3 of SEQ ID NO: 93; (k) HCDR1 of SEQ ID NO: 101, HCDR2 of SEQ ID NO: 102, HCDR3 of SEQ ID NO: 103, LCDR1 of SEQ ID NO: 104, LCDR2 of SEQ ID NO: 105, and LCDR3 of SEQ ID NO: 106; (l) HCDR1 of SEQ ID NO: 111, HCDR2 of SEQ ID NO: 112, HCDR3 of SEQ ID NO: 113, LCDR1 of SEQ ID NO: 114, LCDR2 of SEQ ID NO: 115, and LCDR3 of SEQ ID NO: 116; (m) HCDR1 of SEQ ID NO: 121, HCDR2 of SEQ ID NO: 122, HCDR3 of SEQ ID NO: 123, LCDR1 of SEQ ID NO: 124, LCDR2 of SEQ ID NO: 125, and LCDR3 of SEQ ID NO: 126, or (n) comprises an HCDR1 of SEQ ID NO: 131, an HCDR2 of SEQ ID NO: 132, an HCDR3 of SEQ ID NO: 133, an LCDR1 of SEQ ID NO: 134, an LCDR2 of SEQ ID NO: 135, and an LCDR3 of SEQ ID NO: 136.

[0010] In one embodiment, an antigen binding domain that binds to CD79b comprises LCDR1, LCDR2 and LCDR3. (a) LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; (b) LCDR1 of SEQ ID NO: 14, LCDR2 of SEQ ID NO: 15, and LCDR3 of SEQ ID NO: 16; (c) LCDR1 of SEQ ID NO: 24, LCDR2 of SEQ ID NO: 25, and LCDR3 of SEQ ID NO: 26; (d) LCDR1 of SEQ ID NO: 34, LCDR2 of SEQ ID NO: 35, and LCDR3 of SEQ ID NO: 36; (e) LCDR1 of SEQ ID NO: 44, LCDR2 of SEQ ID NO: 45, and LCDR3 of SEQ ID NO: 46; (f) LCDR1 of SEQ ID NO: 54, LCDR2 of SEQ ID NO: 55, and LCDR3 of SEQ ID NO: 56; (g) LCDR1 of SEQ ID NO: 64, LCDR2 of SEQ ID NO: 65, and LCDR3 of SEQ ID NO: 66; (h) LCDR1 of SEQ ID NO: 74, LCDR2 of SEQ ID NO: 75, and LCDR3 of SEQ ID NO: 76; (i) an LCDR1 of SEQ ID NO: 84, an LCDR2 of SEQ ID NO: 85, and an LCDR3 of SEQ ID NO: 86; (j) LCDR1 of SEQ ID NO: 94, LCDR2 of SEQ ID NO: 95, and LCDR3 of SEQ ID NO: 96; (k) LCDR1 of SEQ ID NO: 104, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 106; (l) LCDR1 of SEQ ID NO: 114, LCDR2 of SEQ ID NO: 115, and LCDR3 of SEQ ID NO: 116; (m) an LCDR1 of SEQ ID NO: 124, an LCDR2 of SEQ ID NO: 125, and an LCDR3 of SEQ ID NO: 126, or (n) comprises an LCDR1 of SEQ ID NO: 134, an LCDR2 of SEQ ID NO: 135, and an LCDR3 of SEQ ID NO: 136.

[0011] In one embodiment, an antigen binding domain that binds to CD79b comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3. (a) HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; (b) HCDR1 of SEQ ID NO: 11, HCDR2 of SEQ ID NO: 12, HCDR3 of SEQ ID NO: 13, LCDR1 of SEQ ID NO: 14, LCDR2 of SEQ ID NO: 15, and LCDR3 of SEQ ID NO: 16; (c) HCDR1 of SEQ ID NO: 21, HCDR2 of SEQ ID NO: 22, HCDR3 of SEQ ID NO: 23, LCDR1 of SEQ ID NO: 24, LCDR2 of SEQ ID NO: 25, and LCDR3 of SEQ ID NO: 26; (d) HCDR1 of SEQ ID NO: 31, HCDR2 of SEQ ID NO: 32, HCDR3 of SEQ ID NO: 33, LCDR1 of SEQ ID NO: 34, LCDR2 of SEQ ID NO: 35, and LCDR3 of SEQ ID NO: 36; (e) HCDR1 of SEQ ID NO: 41, HCDR2 of SEQ ID NO: 42, HCDR3 of SEQ ID NO: 43, LCDR1 of SEQ ID NO: 44, LCDR2 of SEQ ID NO: 45, and LCDR3 of SEQ ID NO: 46; (f) HCDR1 of SEQ ID NO: 51, HCDR2 of SEQ ID NO: 52, HCDR3 of SEQ ID NO: 53, LCDR1 of SEQ ID NO: 54, LCDR2 of SEQ ID NO: 55, and LCDR3 of SEQ ID NO: 56; (g) HCDR1 of SEQ ID NO: 61, HCDR2 of SEQ ID NO: 62, HCDR3 of SEQ ID NO: 63, LCDR1 of SEQ ID NO: 64, LCDR2 of SEQ ID NO: 65, and LCDR3 of SEQ ID NO: 66; (h) HCDR1 of SEQ ID NO: 71, HCDR2 of SEQ ID NO: 72, HCDR3 of SEQ ID NO: 73, LCDR1 of SEQ ID NO: 74, LCDR2 of SEQ ID NO: 75, and LCDR3 of SEQ ID NO: 76; (i) HCDR1 of SEQ ID NO: 81, HCDR2 of SEQ ID NO: 82, HCDR3 of SEQ ID NO: 83, LCDR1 of SEQ ID NO: 84, LCDR2 of SEQ ID NO: 85, and LCDR3 of SEQ ID NO: 86; (j) HCDR1 of SEQ ID NO: 91, HCDR2 of SEQ ID NO: 92, HCDR3 of SEQ ID NO: 93, LCDR1 of SEQ ID NO: 94, LCDR2 of SEQ ID NO: 95, and LCDR3 of SEQ ID NO: 96; (k) HCDR1 of SEQ ID NO: 101, HCDR2 of SEQ ID NO: 102, HCDR3 of SEQ ID NO: 103, LCDR1 of SEQ ID NO: 104, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 106; (l) HCDR1 of SEQ ID NO: 111, HCDR2 of SEQ ID NO: 112, HCDR3 of SEQ ID NO: 113, LCDR1 of SEQ ID NO: 114, LCDR2 of SEQ ID NO: 115, and LCDR3 of SEQ ID NO: 116; (m) HCDR1 of SEQ ID NO: 121, HCDR2 of SEQ ID NO: 122, HCDR3 of SEQ ID NO: 123, LCDR1 of SEQ ID NO: 124, LCDR2 of SEQ ID NO: 125, and LCDR3 of SEQ ID NO: 126, or (n) comprises an HCDR1 of SEQ ID NO: 131, an HCDR2 of SEQ ID NO: 132, an HCDR3 of SEQ ID NO: 133, an LCDR1 of SEQ ID NO: 134, an LCDR2 of SEQ ID NO: 135, and an LCDR3 of SEQ ID NO: 136.

[0012] In one embodiment, an antigen binding domain that binds CD79b comprises a heavy chain variable region (VH), wherein the VH comprises HCDR1, HDR2 and HCDR3. In one embodiment, the VH is selected from the group consisting of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, and SEQ ID NO:137.

[0013] In one embodiment, an antigen binding domain that binds to CD79b comprises a light chain variable region (VL), wherein the VL comprises LCDR1, LDR2 and LCDR3. In one embodiment, the VL is selected from the group consisting of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, and SEQ ID NO:138.

[0014] In one embodiment, the VH is selected from the group consisting of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, and SEQ ID NO:137, and the VL is selected from the group consisting of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, and SEQ ID NO:138. In one embodiment, the antigen binding domain that binds to CD79b is (a) a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8; (b) VH of SEQ ID NO: 17 and VL of SEQ ID NO: 18; (c) VH of SEQ ID NO: 27 and VL of SEQ ID NO: 28; (d) a VH of SEQ ID NO: 37 and a VL of SEQ ID NO: 38; (e) a VH of SEQ ID NO: 47 and a VL of SEQ ID NO: 48; (f) a VH of SEQ ID NO: 57 and a VL of SEQ ID NO: 58; (g) a VH of SEQ ID NO: 67 and a VL of SEQ ID NO: 68; (h) VH of SEQ ID NO: 77 and VL of SEQ ID NO: 78; (i) a VH of SEQ ID NO: 87 and a VL of SEQ ID NO: 88; (j) a VH of SEQ ID NO: 97 and a VL of SEQ ID NO: 98; (k) a VH of SEQ ID NO: 107 and a VL of SEQ ID NO: 108; (l) VH of SEQ ID NO: 117 and VL of SEQ ID NO: 118; (m) a VH of SEQ ID NO: 127 and a VL of SEQ ID NO: 128; or (n) comprises a VH of SEQ ID NO: 137 and a VL of SEQ ID NO: 138.

[0015] In one embodiment, the antigen binding domain that binds to CD79b is an scFv, (scFv)2, Fv, Fab, F(ab')2, Fd, dAb, or VHH. In one embodiment, the antigen binding domain that binds to CD79b is a Fab. In one embodiment, the antigen binding domain that binds to CD79b is a VHH.

[0016] In one embodiment, the antigen-binding domain that binds to CD79b is an scFv. In one embodiment, the scFv comprises, from N-terminus to C-terminus, a VH, a first linker (L1), and a VL (VH-L1-VL), or a VL, L1, and a VH (VL-L1-VH). In one embodiment, L1 comprises about 5 to 50 amino acids, about 5 to 40 amino acids, about 10 to 30 amino acids, or about 10 to 20 amino acids. In one embodiment, L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 141 to SEQ ID NO: 173.

[0017] In one embodiment, the isolated protein is a monospecific protein. In one embodiment, the isolated protein is a multispecific protein. In one embodiment, the multispecific protein is a bispecific protein. In one embodiment, the multispecific protein is a trispecific protein.

[0018] In one embodiment, the isolated protein further comprises an immunoglobulin (Ig) constant region or a fragment of an Ig constant region thereof. In one embodiment, the Ig constant region comprises an Fc region. In one embodiment, the fragment of an Ig constant region comprises a CH2 domain. In one embodiment, the fragment of an Ig constant region comprises a CH3 domain. In one embodiment, the fragment of an Ig constant region comprises a CH2 domain and a CH3 domain. In one embodiment, the fragment of an Ig constant region comprises at least a portion of a hinge, a CH2 domain and a CH3 domain. In one embodiment, the fragment of an Ig constant region comprises a hinge, a CH2 domain, and a CH3 domain.

[0019] In one embodiment, the antigen binding domain that binds CD79b is conjugated to the N-terminus of an Ig constant region or a fragment of an Ig constant region. In one embodiment, the antigen binding domain that binds CD79b is conjugated to the C-terminus of an Ig constant region or a fragment of an Ig constant region.

[0020] In one embodiment, the antigen-binding domain that binds to CD79b is conjugated to an Ig constant region or a fragment of an Ig constant region via a second linker (L2), in one embodiment, L2 comprises the amino acid sequence of SEQ ID NO: 141 to SEQ ID NO: 173.

[0021] In one embodiment, the Ig constant region or fragment of an Ig constant region is of the IgG1, IgG2, IgG3, or IgG4 isotype. In one embodiment, the Ig constant region or fragment of an Ig constant region is of the IgG1 isotype.

[0022] In one embodiment, the Ig constant region or fragment of an Ig constant region comprises at least one mutation that results in reduced binding of the protein to an Fcγ receptor (Fcγ receptor, FcR). In one embodiment, the FcγR is selected from the group consisting of F234A / L235A, L234A / L235A, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, F234A / L235A, S228P / F234A / L235A, N297A, V234A / G237A, K214T / E233P / L234V / L235A / G236 deletion / A327G / P331A / D365E / L35 8M, H268Q / V309L / A330S / P331S, S267E / L328F, L234F / L235E / D265A, L234A / L235A / G237A / P238S / H268A / A330S / P331S, S228P / F234A / L235A / G237A / P238S, and S228P / F234A / L235A / G236 deletion / G237A / P238S, where residue numbering is according to the EU index.

[0023] In one embodiment, the Ig constant region or fragment of the Ig constant region comprises at least one mutation that results in enhanced binding of the protein to Fcγ. In one embodiment, the FcγR is selected from the group consisting of S239D / I332E, S298A / E333A / K334A, F243L / R292P / Y300L, F243L / R292P / Y300L / P396L, F243L / R292P / Y300L / V305I / P396L, and G236A / S239D / I332E, where residue numbering is according to the EU index. In one embodiment, the FcγR is FcγRI, FcγRIIA, FcγRIIB, or FcγRIII, or any combination thereof.

[0024] In one embodiment, the Ig constant region of the fragment of an Ig constant region comprises at least one mutation that modulates the half-life of the protein, hi one embodiment, the at least one mutation that modulates the half-life of the protein is selected from the group consisting of H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E / H433K / N434F, T308P / N434A, and H435R, where residue numbering is according to the EU index.

[0025] In one embodiment, the protein comprises at least one mutation in the CH3 domain of the Ig constant region. In one embodiment, the at least one mutation in the CH3 domain of the Ig constant region is T350V, L351Y, F405A, Y407V, T366Y, T366W, F405W, T394W, T394S, Y407T, Y407A, T366S / L368A / Y407V, L351Y / F405A / Y407V, T366I / K392M / T394W, F405A / and Y407V, T366L / K392M / T394W, L351Y / Y407A, T366A / K409F, L351Y / Y407A, T366V / K409F, T366A / K409F, T350V / L351Y / F405A / Y407V, and T350V / T366L / K392L / T394W, where residue numbering is according to the EU index.

[0026] In one embodiment, the antigen binding domain that binds to CD79b comprises a heavy chain and a light chain, wherein the heavy chain comprises a VH and the light chain comprises a VL. In one embodiment, the HC is selected from the group consisting of SEQ ID NO:9, SEQ ID NO:19, SEQ ID NO:29, SEQ ID NO:39, SEQ ID NO:49, SEQ ID NO:59, SEQ ID NO:69, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:99, SEQ ID NO:109, SEQ ID NO:119, SEQ ID NO:129, or SEQ ID NO:139, and the LC is selected from the group consisting of SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:30, SEQ ID NO:40, SEQ ID NO:50, SEQ ID NO:60, SEQ ID NO:70, SEQ ID NO:80, SEQ ID NO:90, SEQ ID NO:100, SEQ ID NO:110, SEQ ID NO:120, SEQ ID NO:130, or SEQ ID NO:140.

[0027] In one embodiment, the antigen binding domain that binds to CD79b comprises (a) HC of SEQ ID NO: 9 and LC of SEQ ID NO: 10, (b) HC of SEQ ID NO: 19 and LC of SEQ ID NO: 20; (c) HC of SEQ ID NO: 29 and LC of SEQ ID NO: 30; (d) HC of SEQ ID NO: 39 and LC of SEQ ID NO: 40; (e) HC of SEQ ID NO: 49 and LC of SEQ ID NO: 50; (f) HC of SEQ ID NO: 59 and LC of SEQ ID NO: 60; (g) HC of SEQ ID NO: 69 and LC of SEQ ID NO: 70; (h) HC of SEQ ID NO: 79 and LC of SEQ ID NO: 80; (i) HC of SEQ ID NO: 89 and LC of SEQ ID NO: 90; (j) HC of SEQ ID NO: 99 and LC of SEQ ID NO: 100; (k) HC of SEQ ID NO: 109 and LC of SEQ ID NO: 110; (l) HC of SEQ ID NO: 119 and LC of SEQ ID NO: 120; (m) a HC of SEQ ID NO: 129 and a LC of SEQ ID NO: 130; or (n) comprising a HC of SEQ ID NO: 139 and a LC of SEQ ID NO: 140.

[0028] In one aspect, the present disclosure provides an immunoconjugate comprising an isolated protein of the present disclosure conjugated to a therapeutic or imaging agent. In one aspect, the present disclosure provides a pharmaceutical composition comprising an isolated protein of the present disclosure and a pharma- ceutically acceptable carrier.

[0029] In one aspect, the disclosure provides a polynucleotide encoding an isolated protein of the disclosure. In one aspect, the disclosure provides a vector comprising a polynucleotide of the disclosure. In one aspect, the disclosure provides a host cell comprising the vector.

[0030] In one aspect, there is provided a method of producing an isolated protein of the disclosure, the method comprising culturing a host cell of the disclosure under conditions such that the protein is expressed, and harvesting the protein produced by the host cell.

[0031] In one aspect, the present disclosure provides a method comprising administering a therapeutically effective amount of an antigen binding domain that binds CD79b of an isolated protein of this disclosure, an immunoconjugate of this disclosure, or a pharmaceutical composition of this disclosure to a subject with an autoimmune disease.

[0032] In one aspect, the present disclosure provides a method of treating an autoimmune disease in a subject, hi one embodiment, the method comprises administering to the subject a therapeutically effective amount of an antigen binding domain that binds CD79b of an isolated protein of this disclosure, an immunoconjugate of this disclosure, or a pharmaceutical composition of this disclosure for a time sufficient to treat the autoimmune disease.

[0033] In one aspect, the present disclosure provides a method of preventing an autoimmune disease in a subject, hi one embodiment, the method comprises administering to the subject a therapeutically effective amount of an antigen binding domain that binds CD79b of an isolated protein of this disclosure, an immunoconjugate of this disclosure, or a pharmaceutical composition of this disclosure for a time sufficient to prevent the autoimmune disease.

[0034] In one embodiment, the autoimmune disease is associated with or characterized by dysregulation of B cells, autoreactive B cells, or the presence of autoantibodies. In one embodiment, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), Sjogren's syndrome (SjS), rheumatoid arthritis, autoimmune myopathy, type 1 diabetes, Addison's disease, pernicious anemia, autoimmune hepatitis, primary biliary cholangitis (PBC), autoimmune pancreatitis, celiac disease, focal glomerulosclerosis, primary membranous nephropathy, ovarian failure, autoimmune orchitis, dry eye disease, idiopathic interstitial pneumonia, thyroid disease (e.g., Graves' disease), systemic sclerosis (scleroderma), myasthenic syndrome, autoimmune encephalitis, bullous skin disease, TTP, ITP, AIHA, Anca vasculitis, myocarditis / dilated CM, NMOSD, maternal-fetal alloimmunity, maternal-fetal autoimmunity, anticardiolipin / antiphospholipid syndrome, hypergammaglobulinemia, transplant-associated ID, multifocal motor neuropathy.

[0035] In one aspect, the present disclosure provides a method of modulating B cell activation in a subject, hi one embodiment, the method comprises administering to the subject a therapeutically effective amount of an antigen binding domain that binds CD79b of an isolated protein of this disclosure, an immunoconjugate of this disclosure, or a pharmaceutical composition of this disclosure for a time sufficient to modulate B cell activation.

[0036] In one aspect, the present disclosure provides a method of inhibiting aberrant B cell activation in a subject, hi one embodiment, the method comprises administering to the subject a therapeutically effective amount of an antigen binding domain that binds CD79b of an isolated protein of this disclosure, an immunoconjugate of this disclosure, or a pharmaceutical composition of this disclosure for a time sufficient to inhibit aberrant B cell activation.

[0037] In one aspect, the present disclosure provides a kit comprising an isolated protein of this disclosure, an isolated multispecific protein of this disclosure, an immunoconjugate of this disclosure, or a pharmaceutical composition of this disclosure.

[0038] In one aspect, the present disclosure provides an anti-idiotypic antibody that binds to an isolated protein of the present disclosure.

[0039] The disclosed method may be more readily understood by reference to the following detailed description: It is to be understood that the disclosed method is not limited to the specific methods described and / or illustrated herein, and further, the terminology used herein is for the purpose of describing specific embodiments by way of example only, and is not intended to be limiting to the claimed methods.

[0040] All patents, published patent applications and publications cited herein are incorporated by reference as if fully set forth herein.

[0041] When lists are presented, it is to be understood that each individual member of that list and every combination of that list is a separate embodiment, unless otherwise specified. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0042] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.

[0043] The transitional phrases "comprising," "consisting essentially of," and "consisting" are intended to connote their generally accepted meanings in patent language, i.e., (i) "comprising" is synonymous with "comprising," "containing," or "characterized by," is inclusive or open-ended, and does not exclude other unrecited elements or method steps, (ii) "consisting of" excludes any element, step, or ingredient not specified in the claim, and (iii) "consisting essentially of" limits the claim to the materials or steps specified, and those that do not materially affect the "basic and novel characteristics" of the claimed invention. Embodiments described with the phrase "comprising" (or its equivalents) are also provided as embodiments described independently with "consisting of" and "consisting essentially of."

[0044] "About" means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on the limitations of the method, i.e., measurement system, by which the value is measured or determined. In the context of a particular assay, result, or embodiment, unless expressly stated otherwise in the examples or elsewhere in the specification, "about" means within one standard deviation per the practice of the art, or within a range of up to 5%, whichever is greater.

[0045] "Activation", "stimulation", "activated" or "stimulated" refers to the induction of a change in the biological state of a cell that results in the expression of activation markers, cytokine production, proliferation, or mediation of cytotoxicity of a target cell. A cell can be activated by a primary stimulatory signal. A costimulatory signal can amplify the magnitude of the primary signal and inhibit cell death after the initial stimulation, resulting in a more durable activation state and thus a higher cytotoxic potential. A "costimulatory signal" refers to a signal that, in combination with a primary signal such as TCR / CD3 ligation, causes proliferation of T cells and / or natural killer (NK) cells and / or up- or down-regulation of key molecules.

[0046] "Alternative scaffold" refers to a single-chain protein framework that contains a structured core associated with highly conformationally tolerant variable domains that can be engineered and selected to bind specific antigens, allowing for polymorphism to be introduced without compromising the integrity of the scaffold.

[0047] "Antibody-dependent cellular cytotoxicity," "antibody-dependent cell-mediated cytotoxicity," or "ADCC" refers to a mechanism of cell death induction that depends on the interaction of antibody-coated target cells with lytic effector cells, such as NK cells, monocytes, macrophages, and neutrophils, via Fc gamma receptors (FcγR) expressed on the effector cells.

[0048] "Antibody-dependent cellular phagocytosis" or "Antibody-dependent cellular phagocytosis (ADCP)" refers to a mechanism by which antibody-coated target cells are eliminated by internalization by phagocytes, such as macrophages or dendritic cells.

[0049] "Antigen" refers to any molecule (e.g., a protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, portions thereof, or combinations thereof) that can be bound by an antigen-binding domain. Antigens can be expressed by genes from biological samples such as tissue samples, tumor samples, cells, or fluids with other biological components, organisms, protein / antigen subunits, killed or inactivated whole cells or lysates, or can be synthesized from the sample, or purified from the sample.

[0050] "Antigen-binding fragment" or "antigen-binding domain" refers to a portion of a protein that binds to an antigen. Antigen-binding fragments may be synthetic, enzymatically obtainable, or genetically engineered polypeptides, including antigen-binding immunoglobulin portions, such as VH, VL, VH and VL, Fab, Fab', F(ab')2, Fd and Fv fragments, domain antibodies (dAbs) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, VHH domains, minimal recognition units consisting of amino acid residues mimicking the CDRs of an antibody, such as the FR3-CDR3-FR4 portion, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3, alternative scaffolds that bind antigen, and multispecific proteins that include antigen-binding fragments. Antigen-binding fragments (such as VH and VL) can be linked together via synthetic linkers to form various types of single chain antibody designs, where the VH / VL domains can pair intramolecularly or intermolecularly to form monovalent antigen-binding domains, such as single chain Fvs (scFvs) or diabodies, when the VH and VL domains are expressed as separate single chains. Antigen-binding fragments may also be conjugated to other antibodies, proteins, antigen-binding fragments, or alternative scaffolds, which may be monospecific or multispecific, to engineer bispecific and multispecific proteins.

[0051] "Antibody" has a broad meaning and includes monoclonal antibodies, including mouse, human, humanized, and chimeric monoclonal antibodies, antigen-binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific, dimeric, tetrameric, or multimeric antibodies, single-chain antibodies, domain antibodies, and immunoglobulin molecules, including any other modified form of an immunoglobulin molecule that contains an antigen-binding site of the required specificity. A "full-length antibody" is composed of two heavy chains (HC) and two light chains (LC), and multimers thereof (e.g., IgM), interconnected by disulfide bonds. Each HC is composed of a heavy chain variable region (VH) and a heavy chain constant region (consisting of domains CH1, hinge, CH2, and CH3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further divided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with framework regions (FRs). Each VH and VL is composed of three CDR and four FR segments arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Depending on the amino acid sequence of the heavy chain constant domain, immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0052] "Bispecific" refers to a molecule (such as an antibody) that specifically binds to two different antigens, or two different epitopes within the same antigen. Bispecific molecules may be cross-reactive to other related antigens, such as the same antigen (homologs) from other species, such as humans or monkeys, such as cynomolgus monkeys (Macaca cynomolgus, cyno) or chimpanzees (Pan troglodytes), or may bind to epitopes shared between two or more different antigens.

[0053] As used herein, the term "chimeric antigen receptor" (CAR) is defined as a cell surface receptor that contains an extracellular target binding domain, a transmembrane domain, and an intracellular signaling domain, all in a combination not found together in a single protein in nature. This includes receptors whose extracellular domain and intracellular signaling domain are not found together in a single receptor protein in nature. CARs are primarily intended for use in lymphocytes, such as T cells and NK cells.

[0054] "Complement-dependent cytotoxicity" or "Complement-dependent cytotoxicity (CDC)" refers to a mechanism of cell death induction in which the Fc effector domain of a target-bound protein binds and activates the complement component C1q, which in turn activates the complement cascade leading to target cell death. Complement activation can also result in the deposition of complement components on the target cell surface, facilitating CDC through the binding of complement receptors (e.g., CR3) to leukocytes.

[0055] A "complementarity determining region" (CDR) is a region of an antibody that binds to an antigen. There are three CDRs in VH (HCDR1, HCDR2, and HCDR3), and there are three CDRs in VL (LCDR1, LCDR2, and LCDR3). CDRs can be defined using a variety of descriptions, such as Kabat (Wu et al. (1970) J Exp Med 132:211-50; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. (1987) J Mol Biol 196:901-17), IMGT (Lefranc et al. (2003) Dev Comp Immunol 27:55-77), and AbM (Martin and Thornton J Bmol Biol 263:800-15, 1996). Various delineations and their correspondence with the numbering of variable regions have been described (e.g., Lefranc et al. (2003) Dev Comp Immunol 27:55-77; Honegger and Pluckthun, J Mol Biol (2001) 309:657-70; International ImMunoGeneTics (IMGT) database, web resource, www_imgt_org). CDRs can be delineated using available programs such as abYsis by UCL Business PLC. As used herein, the terms "CDR", "HCDR1", "HCDR2", "HCDR3", "LCDR1", "LCDR2" and "LCDR3" include CDRs defined by any of the methods of Kabat, Chothia, IMGT or AbM as described above, unless otherwise expressly stated in the specification.

[0056] "Decrease," "reduce," "lower," "reducing," or "alleviating" generally refers to the ability of a test molecule to mediate a reduced response (i.e., a downstream effect) when compared to a control or vehicle-mediated response. Exemplary responses are T cell expansion, T cell activation, or T cell-mediated tumor cell killing, or binding of a protein to its antigen or receptor and enhanced binding to Fcγ, or enhanced Fc effector function such as enhanced ADCC, CDC, and / or ADCP. The decrease may be a statistically significant difference in the measured response between the test molecule and a control (or vehicle), or an increase in the measured response, such as an increase of about 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 30 fold or more, e.g., a 500, 600, 700, 800, 900, or 1000 fold or more (including all integers above 1 and decimal points therebetween, e.g., 1.5, 1.6, 1.7, 1.8, etc.).

[0057] A "domain antibody", "dAb" or "dAb fragment" refers to an antibody fragment composed of either the VH and VL domains from a single arm of an antibody.

[0058] "Differentiation" refers to the process of decreasing the potency or proliferation of a cell or transitioning a cell into a more developmentally restricted state.

[0059] "Encode" or "encoding" refers to the unique property of a specific sequence of nucleotides in a polynucleotide, such as a gene, cDNA, or mRNA, to serve as a template for the synthesis of other polymers and macromolecules in biological processes, having either a defined sequence of nucleotides (e.g., rRNA, tRNA, and mRNA) or a defined sequence of amino acids, and the biological properties resulting therefrom. Thus, in a cell or other biological system, a gene, cDNA, or RNA codes for a protein when transcription and translation of the mRNA corresponding to that gene produces a protein. Both the coding strand, whose nucleotide sequence is identical to the mRNA sequence, and the non-coding strand, which is used as a template for transcription of a gene or cDNA, may be referred to as encoding the protein or other product of that gene or cDNA.

[0060] "Enhancing," "promoting," "increasing," "expanding," or "improving" generally refers to the ability of a test molecule to mediate a greater response (i.e., a downstream effect) when compared to a control or vehicle-mediated response. Exemplary responses are T cell expansion, T cell activation, or T cell-mediated tumor cell killing, or binding of a protein to its antigen or receptor and enhanced binding to Fcγ, or enhanced Fc effector function such as enhanced ADCC, CDC, and / or ADCP. The enhancement may be a statistically significant difference in the measured response between the test molecule and a control (or vehicle), or an increase in the measured response, such as an increase of about 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 30 fold or more, e.g., a 500, 600, 700, 800, 900, or 1000 fold or more (including all integers above 1 and decimal points therebetween, e.g., 1.5, 1.6, 1.7, 1.8, etc.).

[0061] "Expansion" refers to the result of cell division and cell death.

[0062] "Express" and "expression" refer to the well-known transcription and translation that occurs within a cell or in vitro. Thus, an expression product, e.g., a protein, is expressed by a cell or in vitro and may be an intracellular, extracellular, or transmembrane protein.

[0063] "Expression vector" refers to a vector that can be utilized in a biological system or a reconstituted biological system to direct the translation of a polypeptide encoded by a polynucleotide sequence present in the expression vector. An expression vector contains sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system. Expression vectors include all vectors known in the art, including cosmids incorporating recombinant polynucleotides, plasmids (e.g., naked or contained in liposomes), and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses).

[0064] A "dAb" or "dAb fragment" refers to an antibody fragment composed of a VH domain (Ward et al., Nature 341:544 546 (1989)).

[0065] "Fab" or "Fab fragment" refers to an antibody fragment composed of the VH, CH1, VL, and CL domains.

[0066] "F(ab')2" or "F(ab')2 fragment" refers to an antibody fragment comprising two Fab fragments connected by a disulfide bridge in the hinge region.

[0067] "Fd" or "Fd fragment" refers to an antibody fragment composed of the VH and CH1 domains.

[0068] "Fv" or "Fv fragment" refers to an antibody fragment composed of the VH and VL domains from a single arm of an antibody.

[0069] A "full-length antibody" is composed of two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain is composed of a heavy chain variable domain (VH) and a heavy chain constant domain, which in turn is composed of the subdomains CH1, hinge, CH2, and CH3. Each light chain is composed of a light chain variable domain (VL) and a light chain constant domain (CL). VH and VL can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), interspersed with framework regions (FRs). Each VH and VL is composed of three CDR and four FR segments, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0070] "Genetic modification" refers to the introduction of a "foreign" (i.e., exogenous or extracellular) gene, DNA, or RNA sequence into a host cell such that the host cell expresses the introduced gene or sequence to produce a desired substance, typically a protein or enzyme encoded by the introduced gene or sequence. The introduced gene or sequence may also be referred to as a "cloned" or "foreign" gene or sequence and may include regulatory or control sequences operably linked to the polynucleotide encoding the chimeric antigen receptor, such as start, stop, promoter, signal, secretion, or other sequences used by the genetic machinery of the cell. The gene or sequence may include non-functional sequences that have no known function. A host cell that receives and expresses the introduced DNA or RNA is "genetically engineered." The DNA or RNA introduced into a host cell may be from any source, including cells of the same genus or species as the host cell, or from a different genus or species.

[0071] "Heterologous" refers to two or more polynucleotides or two or more polypeptides that are not found in the same relationship to each other in nature.

[0072] "Heterologous polynucleotide" refers to a non-naturally occurring polynucleotide that encodes two or more neo-antigens described herein.

[0073] "Heterologous polypeptide" refers to a non-naturally occurring polypeptide that comprises two or more neo-antigen polypeptides described herein.

[0074] "Host cell" refers to any cell that contains a heterologous nucleic acid. An exemplary heterologous nucleic acid is a vector (e.g., an expression vector).

[0075] "Human antibody" refers to an antibody that is optimized to minimize immune responses when administered to a human subject. The variable regions of a human antibody are derived from human immunoglobulin sequences. If the human antibody contains a constant region or a portion of a constant region, the constant region is also derived from a human immunoglobulin sequence. A human antibody contains heavy and light chain variable regions that are "derived" from sequences of human origin when the variable regions of the human antibody are derived from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Exemplary such systems are phage-displayed human immunoglobulin gene libraries and transgenic non-human animals, such as mice or rats, carrying human immunoglobulin loci. "Human antibodies" typically contain amino acid differences when compared to immunoglobulins expressed in humans, due to differences in the system used to obtain the human antibodies and human immunoglobulin loci, the deliberate introduction of somatic mutations or substitutions into the framework or CDRs, or both. Typically, a "human antibody" is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to the amino acid sequence encoded by a human germline immunoglobulin or rearranged immunoglobulin gene. In some cases, a "human antibody" may contain a consensus framework sequence derived from human framework sequence analysis as described, for example, in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into a library of human immunoglobulin genes displayed on phage as described, for example, in Shi et al., (2010) J Mol Biol 397:385-96 and WO 2009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of "human antibody."

[0076] A "humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. Humanized antibodies can contain substitutions in the framework, such that the framework may not be an exact copy of an expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0077] "In combination with" means that two or more therapeutic agents are administered to a subject together in a mixture, simultaneously as single agents, or sequentially in any order as single agents.

[0078] "Isolated" refers to a homogenous population of molecules that have been substantially separated and / or purified away from other components of the system in which they are produced, such as in a recombinant cell (e.g., a synthetic polynucleotide or polypeptide), as well as to a protein that has been subjected to at least one purification or isolation step. "Isolated" refers to molecules that are substantially free of other cellular material and / or chemicals, and includes molecules that have been isolated to greater degrees of purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0079] "Cluster of Differentiation CD79B protein" or "CD79b" refers to the known protein also known as CD79b. The amino acid sequences of the various isoforms are available under GenBank Accession Nos. AAH32651.1, EAW94232.1, AAH02975.2, NP_000617.1, and NP_001035022.1. The amino acid sequence of the full length CD79b sequence is shown below. The sequence includes the extracellular domain (residues 29-159) and the cytoplasmic domain (residues 181-229). MARLALSPVPSHWMVALLLLLSAEPVPAARSEDRYRNPKGSACSRIWQSPRFIARKRGFTVKMHCYMNSASGNVSWLWKQEMDENPQQLKLEKGRMEESQNESLATLTIQGIRFEDNGIYFCQQKCNNTSEVYQGCGTELRVMGFSTLAQLKQRNTLKDGIIMIQTLLIILFIIVPIFLLLDKDDSKAGMEEDHTYEGLDIDQTATYEDIVTLRTGEVKWSVGEHPGQE (SEQ ID NO: 177)

[0080] "Modulate" refers to either an enhanced or decreased ability of the test molecule to mediate a greater or lesser response (i.e., a downstream effect) when compared to a control or vehicle-mediated response.

[0081] By "monoclonal antibody" is meant an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., individual antibodies that make up the population, that are identical except for possible well-known alterations, such as removal of the C-terminal lysine from the antibody heavy chain, or post-translational modifications such as isomerization or deamidation of amino acids, oxidation of methionine, or deamidation of asparagine or glutamine. A monoclonal antibody typically binds to one antigenic epitope. A bispecific monoclonal antibody binds to two different antigenic epitopes. A monoclonal antibody may have heterogeneous glycosylation within the antibody population. A monoclonal antibody may be monospecific or multispecific, such as bispecific, and may be monovalent, bivalent, or multivalent.

[0082] "Minibody" refers to scFv fragments linked via CH3 domains.

[0083] "Multispecific" refers to a molecule, such as an antibody, that specifically binds to two or more different antigens, or to two or more different epitopes within the same antigen. Multispecific molecules may be cross-reactive to other related antigens, e.g., the same antigen (homologs) from other species, such as humans or monkeys, e.g., Macaca fascicularis (cynomolgus, cyno) or chimpanzees (Pan troglodytes), or may bind to epitopes shared between two or more different antigens.

[0084] "Natural killer cells" and "NK cells" are used interchangeably and synonymously herein. As used herein, NK cells are cells that express the CD16 + CD56 + and / or CD57 + TCR - NK cells refer to differentiated lymphocytes with a phenotype characterized by the ability to bind to and kill cells that fail to express "self" MHC / HLA antigens by activation of specific cytolytic enzymes, to kill tumor cells or other diseased cells that express ligands for NK activating receptors, and to release protein molecules called cytokines that stimulate or inhibit the immune response.

[0085] "Operably linked" and similar phrases, when used with respect to nucleic acids or amino acids, refer to the operative linkage of nucleic acid or amino acid sequences, respectively, placed in a functional relationship with each other. For example, operably linked promoters, enhancer elements, open reading frames, 5' and 3' UTRs, and terminator sequences result in the correct production of a nucleic acid molecule (e.g., RNA), and in some cases, the production of a polypeptide (i.e., expression of the open reading frame). "Operably linked peptides" refer to peptides in which the functional domains of the peptide are positioned at an appropriate distance from each other to confer the intended function of each domain.

[0086] A "pharmaceutical combination" refers to a combination of two or more active ingredients administered together or separately.

[0087] A "pharmaceutical composition" refers to a composition obtained by combining active ingredients with a pharma- ceutically acceptable carrier.

[0088] A "pharmaceutically acceptable carrier" or "excipient" refers to an ingredient in a pharmaceutical composition, other than an active ingredient, that is not toxic to a subject. Exemplary pharmaceutically acceptable carriers are buffers, stabilizers, or preservatives.

[0089] "Polynucleotide" or "nucleic acid" refers to a synthetic molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. cDNA is a typical example of a polynucleotide. A polynucleotide can be a DNA or RNA molecule.

[0090] "Preventing," "preventing," "prevention," or "prophylaxis" of a disease or disorder means barring the occurrence of the disorder in a subject.

[0091] "Proliferation" refers to an increase in cell division, either symmetric or asymmetric division of cells.

[0092] "Promoter" refers to a minimal sequence necessary to initiate transcription. A promoter can also contain enhancer or repressor elements that enhance or repress, respectively, transcription.

[0093] "Protein" or "polypeptide", as used interchangeably herein, refers to a molecule that includes one or more polypeptides, each composed of at least two amino acid residues linked by a peptide bond. A protein may be a monomer or a protein complex of two or more subunits, which may be the same or different. Small polypeptides consisting of less than 50 amino acids may be referred to as "peptides". A protein may be a heterologous fusion protein, a glycoprotein, or a protein modified by post-translational modifications such as phosphorylation, acetylation, myristoylation, palmitoylation, glycosylation, oxidation, formylation, amidation, citrullination, polyglutamylation, ADP-ribosylation, pegylation, or biotinylation. A protein may be recombinantly expressed.

[0094] "Recombinant" refers to polynucleotides, polypeptides, vectors, viruses, and other macromolecules that are prepared, expressed, created, or isolated by recombinant means.

[0095] "Regulatory element" refers to any cis- or trans-acting genetic element that controls some aspect of the expression of nucleic acid sequences.

[0096] "Relapse" refers to the return of a disease or signs and symptoms of a disease after a period of improvement following previous treatment with a therapeutic agent.

[0097] "Refractory" refers to a disease that does not respond to treatment. A refractory disease can be resistant to treatment before or at the start of treatment, or a refractory disease can become resistant during treatment.

[0098] "Single-chain Fv" or "scFv" refers to a fusion protein comprising at least one antibody fragment comprising a light chain variable region (VL) and at least one antibody fragment comprising a heavy chain variable region (VH), where the VL and VH are contiguously linked via a polypeptide linker and can be expressed as a single-chain polypeptide. Unless otherwise specified, as used herein, an scFv can have the VL and VH variable regions in either order, e.g., with respect to the N-terminus and C-terminus of the polypeptide, an scFv can comprise VL-linker-VH or VH-linker-VL.

[0099] "Specifically binds," "specific binding," "specifically binding," or "binds" refers to a proteinaceous molecule binding to an antigen or an epitope within an antigen with higher affinity than its affinity for other antigens. Typically, a proteinaceous molecule binds to an antigen with an affinity of about 1×10 -7 M or less, e.g., about 5×10 -8 M or less, approximately 1×10 -8 M or less, approximately 1×10 -9 M or less, approximately 1×10 -10 M or less, approximately 1×10 -11 M or less, or about 1 x 10 -12 The equilibrium dissociation constant (K D ) binds to an antigen or an epitope within an antigen, typically D is the K for binding to non-specific antigens (e.g., BSA, casein) D In the context of the CD79b antigen described herein, "specific binding" refers to binding of a proteinaceous molecule to the CD79b antigen without detectably binding to the wild-type protein of which the CD79b antigen is a variant.

[0100] A "subject" includes any human or non-human animal. A "non-human animal" includes any vertebrate, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" may be used interchangeably herein.

[0101] "T cell" and "T lymphocyte" are interchangeable and are used synonymously herein. T cells include thymocytes, naive T lymphocytes, memory T cells, immature T lymphocytes, mature T lymphocytes, resting T lymphocytes, or activated T lymphocytes. T cells can be T helper (Th) cells, e.g., T helper 1 (Th1) or T helper 2 (Th2) cells. T cells can be helper T cells (HT1, CD4 + T cells), CD4 + T cells, cytotoxic T cells (CTL, CD8 + T cells), tumor-infiltrating cytotoxic T cells (TIL, CD8 + T cells), CD4 + CD8 + They may be T cells, or any other subset of T cells. Also included are "NKT cells," which refers to a specialized population of T cells that not only express the semi-invariant αβ T cell receptor, but also express various molecular markers typically associated with NK cells, such as NK1.1. NKT cells include + and NK1.1 - , and CD4 + , CD4 - , CD8 + , and CD8 - NKT cells include T cells. The TCR of NKT cells is unique in that it recognizes glycolipid antigens presented by the MHC I-like molecule CD Id. NKT cells can have either protective or detrimental effects due to their ability to produce cytokines that promote either inflammation or immune tolerance. Also included are "gamma delta T cells (γδ T cells)", which refers to a specialized population of a small subset of T cells that have a different TCR on their surface; unlike the majority of T cells, whose TCR is composed of two glycoprotein chains designated α and β-TCR chains, the TCR in γδ T cells is composed of a γ chain and a δ chain. γδ T cells can play a role in immune surveillance and immune regulation, and are an important source of IL-17, and are potent CD8 +It has been found that the T cells induce cytotoxic T cell responses. Also included is "regulatory T cells" or "Tregs", which refers to T cells that suppress abnormal or excessive immune responses and play a role in immune tolerance. Tregs are typically CD4+ T cells that express the transcription factor Foxp3. + T cells and IL-10-producing CD4 + It may also include T cells, transcription factor Foxp3 negative regulatory T cells.

[0102] "Therapeutically effective amount" or "effective amount", as used interchangeably herein, refers to an amount effective, at the dosage and duration required, to obtain the desired therapeutic result. The therapeutically effective amount may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, an improvement in the patient's health, a reduction in tumor burden, a halt or slowdown in the growth of a tumor, and / or the absence of metastasis of cancer cells to other locations in the body.

[0103] "Transduction" refers to the introduction of exogenous nucleic acid into a cell using a viral vector.

[0104] "Treating," "treating," or "treatment" of a disease or disorder, such as cancer, refers to achieving one or more of the following: reducing the severity and / or duration of the disorder, inhibiting the worsening of symptoms characteristic of the disorder being treated, limiting or preventing the recurrence of the disorder in a subject who previously had the disorder, or limiting or preventing the recurrence of symptoms in a subject who previously had symptoms of the disorder.

[0105] "Variant," "mutant," or "altered" refers to a polypeptide or polynucleotide that differs from a reference polypeptide or polynucleotide by one or more modifications, e.g., one or more substitutions, insertions, or deletions.

[0106] Throughout this specification, the numbering of amino acid residues in antibody constant regions is according to the EU index as set forth in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), unless otherwise expressly stated herein.

[0107] The Ig constant region mutations are designated as follows: L351Y_F405A_Y407V refers to the L351Y, F405A and Y407V mutations in one immunoglobulin constant region, and L351Y_F405A_Y407V / T394W refers to the L351Y, F405A and Y407V mutations in a first Ig constant region and the T394W mutation in a second Ig constant region present in one multimeric protein.

[0108] CD79b-binding domain Thus, antibodies or antigen-binding domains targeting CD79B can deliver drugs to the BCR complex. Thus, CD79B-targeting molecules are useful in the generation of bispecific drugs to recruit naturally occurring inhibitory proteins to the BCR complex to inhibit abnormal B cell activation. For example, bispecific dual affinity retargeting (DART) molecules with antigen-binding domains that recognize both CD79B and the inhibitory Fc gamma receptor CD32B inhibit B cell activation as monitored by reduced B cell proliferation and immunoglobulin secretion. Similar bispecific molecules that recognize both CD79b and CD32B delay onset and reduce disease severity in preclinical models of autoimmune arthritis, indicating that CD79b-mediated recruitment of inhibitory proteins to the BCR may provide therapeutic benefit to patients with autoimmune disease (Veri et al., 2010, Arthritis & Rheumatism, 62:1933-1943). CD79B-targeting bispecific antibodies or antigen-binding domains may also target other inhibitory molecules expressed on the surface of B cells, such as CD22 and members of the Siglec family, such as Siglec-10, which have been demonstrated to inhibit BCR-mediated signaling (reviewed in Duan & Paulson 2020, Ann. Rev Immunol 38(1):365-369).

[0109] CD79B targeting antibodies or antigen binding domains may also be useful in the treatment of various forms of cancer. For example, the anti-CD79b antibody-drug conjugate polatuzumab vedotin has been approved for the treatment of patients with diffuse large B-cell lymphoma (DLBCL) (reviewed in Walji 2020, PMID:32700586; DOI:10.1080 / 17474086.2020-1795828). Furthermore, engineered T cells expressing a chimeric antigen receptor that binds CD79B (CAR T cells) eliminated CD79B-expressing B cell lymphoma cells in vitro and in vivo (Ding 2020, PMID:32495161 DOI:10.1007 / s11523-020-00729-7; Jiang 2020, PMID:31624374 DOI:10.1038 / s41375-019-0607-5; Ormhoj2019, PMID:31439577 PMCID:PMC6891163 DOI:10.1158 / 1078-0432.CCR-19-1337).

[0110] Material composition Antigen-binding domain that binds to CD79b The present disclosure provides antigen binding domains that bind CD79b, monospecific and multispecific proteins comprising an antigen binding domain that binds CD79b, chimeric antigen receptors (CARs) comprising an antigen binding domain that binds CD79b, polynucleotides encoding the same, vectors, host cells, and methods of making and using the same.

[0111] The present disclosure provides an isolated protein comprising an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b). In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131.

[0112] In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132.

[0113] In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0114] In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), wherein the antigen binding domain that binds to CD79b comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121 or SEQ ID NO:131, an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122 or SEQ ID NO:132, and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123 or SEQ ID NO:133.

[0115] In one embodiment, the isolated protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b is HCDR1, HCDR2, and HCDR3 of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:101, SEQ ID NO:102, and SEQ ID NO:103, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:121, SEQ ID NO:122, and SEQ ID NO:123, respectively; or Each comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO:131, SEQ ID NO:132, and SEQ ID NO:133, respectively.

[0116] In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134.

[0117] In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135.

[0118] In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0119] In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), wherein the antigen binding domain that binds to CD79b comprises an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0120] In one embodiment, the isolated protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b is LCDR, LCDR2, and LCDR3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; the LCDR, LCDR2, and LCDR3 of SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or They comprise the LCDR, LCDR2, and LCDR3 of SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0121] In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131, an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132, and an HCDR2 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:1 03, SEQ ID NO:113, SEQ ID NO:123 or SEQ ID NO:133; LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124 or SEQ ID NO:134; LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125 or SEQ ID NO:135; and LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126 or SEQ ID NO:136.

[0122] In one embodiment, the isolated protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b is HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each of them contains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136.

[0123] In one embodiment, the isolated protein comprises an antigen binding domain that binds CD79b, and the antigen binding domain that binds CD79b comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, SEQ ID NO, or SEQ ID NO:137.

[0124] In one embodiment, the isolated protein comprises an antigen binding domain that binds CD79b, and the antigen binding domain that binds CD79b comprises a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0125] In one embodiment, the isolated protein comprises an antigen binding domain that binds CD79b, wherein the antigen binding domain that binds CD79b comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, SEQ ID NO:, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0126] In one embodiment, the isolated protein comprises an antigen binding domain that binds CD79b, wherein the antigen binding domain that binds CD79b is VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or They comprise the VH and VL of SEQ ID NO: 137 and SEQ ID NO: 138, respectively.

[0127] In one embodiment, the isolated protein comprises an antigen binding domain that binds CD79b, and the antigen binding domain that binds CD79b comprises a heavy chain (HC) of SEQ ID NO:9, SEQ ID NO:19, SEQ ID NO:29, SEQ ID NO:39, SEQ ID NO:49, SEQ ID NO:59, SEQ ID NO:69, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:99, SEQ ID NO:109, SEQ ID NO:119, SEQ ID NO:129, or SEQ ID NO:139.

[0128] In one embodiment, the isolated protein comprises an antigen binding domain that binds CD79b, and the antigen binding domain that binds CD79b comprises a light chain (LC) of SEQ ID NO: 10, SEQ ID NO: 20, SEQ ID NO: 30, SEQ ID NO: 40, SEQ ID NO: 50, SEQ ID NO: 60, SEQ ID NO: 70, SEQ ID NO: 80, SEQ ID NO: 90, SEQ ID NO: 100, SEQ ID NO: 110, SEQ ID NO: 120, SEQ ID NO: 130, or SEQ ID NO: 140.

[0129] In one embodiment, the isolated protein comprises an antigen binding domain that binds CD79b, wherein the antigen binding domain that binds CD79b comprises a HC of SEQ ID NO:9, SEQ ID NO:19, SEQ ID NO:29, SEQ ID NO:39, SEQ ID NO:49, SEQ ID NO:59, SEQ ID NO:69, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:99, SEQ ID NO:109, SEQ ID NO:119, SEQ ID NO:129, or SEQ ID NO:139, and a LC of SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:30, SEQ ID NO:40, SEQ ID NO:50, SEQ ID NO:60, SEQ ID NO:70, SEQ ID NO:80, SEQ ID NO:90, SEQ ID NO:100, SEQ ID NO:110, SEQ ID NO:120, SEQ ID NO:130, or SEQ ID NO:140.

[0130] In one embodiment, the isolated protein comprises an antigen binding domain that binds CD79b, wherein the antigen binding domain that binds CD79b is HC and LC of SEQ ID NO:9 and SEQ ID NO:10, respectively; HC and LC of SEQ ID NO:19 and SEQ ID NO:20, respectively; HC and LC of SEQ ID NO:29 and SEQ ID NO:30, respectively; HC and LC of SEQ ID NO:39 and SEQ ID NO:40, respectively; HC and LC of SEQ ID NO:49 and SEQ ID NO:50, respectively; HC and LC of SEQ ID NO:59 and SEQ ID NO:60, respectively; HC and LC of SEQ ID NO:69 and SEQ ID NO:70, respectively; HC and LC of SEQ ID NO:79 and SEQ ID NO:80, respectively; HC and LC of SEQ ID NO:89 and SEQ ID NO:90, respectively; HC and LC of SEQ ID NO:99 and SEQ ID NO:100, respectively; HC and LC of SEQ ID NO:109 and SEQ ID NO:110, respectively; HC and LC of SEQ ID NO:119 and SEQ ID NO:120, respectively; HC and LC of SEQ ID NO: 129 and SEQ ID NO: 130, respectively; or They contain the HC and LC of SEQ ID NO:139 and SEQ ID NO:140, respectively.

[0131] In some embodiments, the antigen binding domain that binds to CD79b is an scFv.

[0132] In some embodiments, the antigen binding domain that binds to CD79b is (scFv)2.

[0133] In some embodiments, the antigen binding domain that binds to CD79b is an Fv.

[0134] In some embodiments, the antigen binding domain that binds to CD79b is a Fab.

[0135] In some embodiments, the antigen binding domain that binds to CD79b is F(ab')2.

[0136] In some embodiments, the antigen binding domain that binds to CD79b is Fd.

[0137] In some embodiments, the CD79b antigen binding domain is a dAb.

[0138] In some embodiments, the CD79b antigen binding domain is a VHH.

[0139] Multispecific Proteins In some embodiments, the disclosure provides a multispecific protein (e.g., a multispecific antibody) that comprises an antigen-binding domain that binds to CDR79b.For example, in one embodiment, the antigen binding domain that binds to CD79b is selected from the group consisting of dual variable domain immunoglobulins (DVDs) (WO 2009 / 134776, where a DVD is a full-length antibody comprising a heavy chain with the structure VH1-linker-VH2-CH and a light chain with the structure VL1-linker-VL2-CL, where the linker is optional), structures comprising various dimerization domains for linking two antibody arms with different specificities, e.g., leucine zippers or collagen dimerization domains (WO 2012 / 022811, U.S. Pat. No. 5,932,448, U.S. Pat. No. 6,833,441), heavy chain only antibodies such as two or more domain antibodies (dAbs) conjugated together, diabodies, camelid antibodies and genetically engineered camelid antibodies, Dual Targeting (DT)-Ig (GSK / Domantis), Two-in-one Antibody (Genentech), Cross-linked Mab (Karmanos Cancer Center), mAb2 (F-Star) and CovX-body (CovX / Pfizer), IgG-like Bispecific (InnClone / Eli Lilly), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc Fusions (Academic Institution), SCORPION (Emergent Bivalent Bispecific (Biotecnol) and Fab-Fv (UCB-Celltech).ScFv antibodies, diabody-based antibodies, and domain antibodies include, but are not limited to, Bispecific T Cell Engager (BiTE) (Micromet), Tandem Diabody (Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (MacroGenics), single chain diabodies (Academic), TCR-like antibodies (AIT, ReceptorLogics), human serum albumin ScFv fusions (Merrimack), and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain only domain antibodies.

[0140] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b). In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131.

[0141] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132.

[0142] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0143] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), wherein the antigen binding domain that binds to CD79b comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121 or SEQ ID NO:131, an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122 or SEQ ID NO:132, and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123 or SEQ ID NO:133.

[0144] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b is HCDR1, HCDR2, and HCDR3 of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:101, SEQ ID NO:102, and SEQ ID NO:103, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:121, SEQ ID NO:122, and SEQ ID NO:123, respectively; or Each comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO:131, SEQ ID NO:132, and SEQ ID NO:133, respectively.

[0145] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134.

[0146] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135.

[0147] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0148] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), wherein the antigen binding domain that binds to CD79b comprises an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124 or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125 or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126 or SEQ ID NO:136.

[0149] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b is LCDR, LCDR2, and LCDR3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; the LCDR, LCDR2, and LCDR3 of SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or They comprise the LCDR, LCDR2, and LCDR3 of SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0150] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), wherein the antigen binding domain that binds to CD79b comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121 or SEQ ID NO:131 and an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122 or SEQ ID NO:132 and an HCDR2 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO: 103, SEQ ID NO:113, SEQ ID NO:123 or SEQ ID NO:133; LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124 or SEQ ID NO:134; LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125 or SEQ ID NO:135; and LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126 or SEQ ID NO:136.

[0151] In one embodiment, the multispecific protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b is HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each of them contains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136.

[0152] In one embodiment, the multispecific protein comprises an antigen binding domain that binds CD79b, and the antigen binding domain that binds CD79b comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, SEQ ID NO:, or SEQ ID NO:137.

[0153] In one embodiment, the multispecific protein comprises an antigen binding domain that binds CD79b, and the antigen binding domain that binds CD79b comprises a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0154] In one embodiment, the multispecific protein comprises an antigen binding domain that binds CD79b, wherein the antigen binding domain that binds CD79b comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, SEQ ID NO:, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0155] In one embodiment, the multispecific protein comprises an antigen binding domain that binds CD79b, wherein the antigen binding domain that binds CD79b is VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or They comprise the VH and VL of SEQ ID NO: 137 and SEQ ID NO: 138, respectively.

[0156] In one embodiment, an antigen binding domain that binds CD79b is incorporated into a dual affinity retargeting technology (DART) protein. In one aspect, an antigen binding domain that binds CD79B can be incorporated into a DART protein. In a particular aspect, a DART protein comprises two heterodimerized Fv fragments that form two unique antigen binding sites. In one embodiment, a DART comprises a first Fv comprising a VH derived from a first antigen binding domain (VH1) and a VL derived from a second antigen binding domain (VL2). In one embodiment, a DART comprises a second Fv comprising a VH derived from a second antigen binding domain (VH2) and a VL derived from a first antigen binding domain (VL1).

[0157] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b). In one embodiment, the isolated protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131.

[0158] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132.

[0159] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises the HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0160] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131; an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132; and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0161] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b is HCDR1, HCDR2, and HCDR3 of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:101, SEQ ID NO:102, and SEQ ID NO:103, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:121, SEQ ID NO:122, and SEQ ID NO:123, respectively; or Each comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO:131, SEQ ID NO:132, and SEQ ID NO:133, respectively.

[0162] In one embodiment, the DART protein comprises an antigen binding domain that binds to the Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134.

[0163] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135.

[0164] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0165] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an HCDR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0166] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b is LCDR, LCDR2, and LCDR3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; the LCDR, LCDR2, and LCDR3 of SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or They comprise the LCDR, LCDR2, and LCDR3 of SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0167] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121 or SEQ ID NO:131, an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122 or SEQ ID NO:132, and an HCDR2 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO: 103, SEQ ID NO:113, SEQ ID NO:123 or SEQ ID NO:133; LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124 or SEQ ID NO:134; LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125 or SEQ ID NO:135; and LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126 or SEQ ID NO:136.

[0168] In one embodiment, the DART protein comprises an antigen binding domain that binds to Cluster of Differentiation CD79B protein (CD79b), and the antigen binding domain that binds to CD79b is HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0169] In one embodiment, the DART protein comprises an antigen binding domain that binds CD79b, and the antigen binding domain that binds CD79b comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, SEQ ID NO:, or SEQ ID NO:137.

[0170] In one embodiment, the DART protein comprises an antigen binding domain that binds CD79b, and the antigen binding domain that binds CD79b comprises a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0171] In one embodiment, a DART protein comprises an antigen binding domain that binds CD79b, wherein the antigen binding domain that binds CD79b comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, SEQ ID NO:, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0172] In one embodiment, the DART protein comprises an antigen binding domain that binds CD79b, wherein the antigen binding domain that binds CD79b is VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or They comprise the VH and VL of SEQ ID NO: 137 and SEQ ID NO: 138, respectively.

[0173] CD79b binding scFv Any of the VH and VL domains identified herein that bind CD79b can be engineered into scFv formats in either a VH-linker-VL or VL-linker-VH orientation. Any of the VH and VL domains identified herein can also be used to generate sc(FV)2 structures such as VH-linker-VL-linker-VL-linker-VH, VH-linker-VL-linker-VH-linker-VL, VH-linker-VH-linker-VL-linker-VL, VL-linker-VH-linker-VH-linker-VL, VL-linker-VH-linker-VH-linker-VL, VL-linker-VH-linker-VL, VL-linker-VH-linker-VL-linker-VH, or VL-linker-VL-linker-VH-linker-VH.

[0174] The VH and VL domains identified herein can be incorporated into an scFv format and the binding and thermal stability of the resulting scFv to CD79b can be assessed using known methods. Binding can be assessed using ProteOn XPR36, Biacore3000, or KinExA instruments, ELISA, or competitive binding assays known to those skilled in the art. Binding can be assessed using purified scFv or E. coli supernatants, or lysed cells containing the expressed scFv. The measured affinity of a test scFv to CD79b may differ when measured under different conditions (e.g., osmolality, pH). Thus, affinity and other binding parameters (e.g., K D , K on , K off ) is typically performed under standard conditions and using standardized buffers. Thermostability may be assessed by heating a test scFv at an elevated temperature, such as 50° C., 55° C., or 60° C., for a period of time, such as 5, 10, 15, 20, 25, or 30 minutes, and measuring the binding of the test scFv to CD79b. scFvs that retain comparable binding to CD79b when compared to non-heated scFv samples are said to be thermostable.

[0175] In recombinant expression systems, the linker is a peptide linker and may include any naturally occurring amino acid. Exemplary amino acids that may be included in the linker are Gly, Ser, Pro, Thr, Glu, Lys, Arg, Ile, Leu, His, and The. The linker must be of an appropriate length to link the VH and VL in such a way that they form the correct conformation relative to each other so as to retain the desired activity, such as binding to CD79b.

[0176] The linker can be about 5-50 amino acids long. In some embodiments, the linker is about 10-40 amino acids long. In some embodiments, the linker is about 10-35 amino acids long. In some embodiments, the linker is about 10-30 amino acids long. In some embodiments, the linker is about 10-25 amino acids long. In some embodiments, the linker is about 10-20 amino acids long. In some embodiments, the linker is about 15-20 amino acids long. In some embodiments, the linker is 6 amino acids long. In some embodiments, the linker is 7 amino acids long. In some embodiments, the linker is 8 amino acids long. In some embodiments, the linker is 9 amino acids long. In some embodiments, the linker is 10 amino acids long. In some embodiments, the linker is 11 amino acids long. In some embodiments, the linker is 12 amino acids long. In some embodiments, the linker is 13 amino acids long. In some embodiments, the linker is 14 amino acids long. In some embodiments, the linker is 15 amino acids long. In some embodiments, the linker is 16 amino acids long. In some embodiments, the linker is 17 amino acids long. In some embodiments, the linker is 18 amino acids long. In some embodiments, the linker is 19 amino acids long. In some embodiments, the linker is 20 amino acids long. In some embodiments, the linker is 21 amino acids long. In some embodiments, the linker is 22 amino acids long. In some embodiments, the linker is 23 amino acids long. In some embodiments, the linker is 24 amino acids long. In some embodiments, the linker is 25 amino acids long. In some embodiments, the linker is 26 amino acids long. In some embodiments, the linker is 27 amino acids long. In some embodiments, the linker is 28 amino acids long. In some embodiments, the linker is 29 amino acids long.In some embodiments, the linker is 30 amino acids long. In some embodiments, the linker is 31 amino acids long. In some embodiments, the linker is 32 amino acids long. In some embodiments, the linker is 33 amino acids long. In some embodiments, the linker is 34 amino acids long. In some embodiments, the linker is 35 amino acids long. In some embodiments, the linker is 36 amino acids long. In some embodiments, the linker is 37 amino acids long. In some embodiments, the linker is 38 amino acids long. In some embodiments, the linker is 39 amino acids long. In some embodiments, the linker is 40 amino acids long. Exemplary linkers that may be used are Gly-rich linkers, Gly and Ser-containing linkers, Gly and Ala-containing linkers, Ala and Ser-containing linkers, and other flexible linkers.

[0177] Other linker sequences may include portions of the immunoglobulin hinge region, CL or CH1, derived from immunoglobulin heavy or light chain isotypes. Alternatively, various non-proteinaceous polymers may find use as linkers, including polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol. Additional linkers are described, for example, in WO 2019 / 060695.

[0178] In some embodiments, the scFv comprises, from N-terminus to C-terminus, a VH, a first linker (L1), and a VL (VH-L1-VL). In some embodiments, the scFv comprises, from N-terminus to C-terminus, a VL, L1, and a VH (VL-L1-VH).

[0179] In some embodiments, the scFV comprises heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131.

[0180] In some embodiments, the scFv comprises HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132.

[0181] In some embodiments, the scFv comprises an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0182] In some embodiments, the scFv comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131; an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132; and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0183] In some embodiments, the scFv HCDR1, HCDR2, and HCDR3 of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:101, SEQ ID NO:102, and SEQ ID NO:103, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:121, SEQ ID NO:122, and SEQ ID NO:123, respectively; or Each comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO:131, SEQ ID NO:132, and SEQ ID NO:133, respectively.

[0184] In some embodiments, the scFV comprises light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134.

[0185] In some embodiments, the scFv comprises an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135.

[0186] In some embodiments, the scFv comprises an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0187] In some embodiments, the scFv comprises an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0188] In some embodiments, the scFv LCDR, LCDR2, and LCDR3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; the LCDR, LCDR2, and LCDR3 of SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or They comprise the LCDR, LCDR2, and LCDR3 of SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0189] In some embodiments, the scFv comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131, an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132, and an HCDR2 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133. and an HCDR3 and an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0190] In some embodiments, the scFv comprises: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0191] In some embodiments, the scFv comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137.

[0192] In some embodiments, the scFv comprises a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0193] In some embodiments, the Fv comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0194] In some embodiments, the scFv comprises: VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or They comprise the VH and VL of SEQ ID NO: 137 and SEQ ID NO: 138, respectively.

[0195] Other antigen-binding domains that bind to CD79b Any of the VH and VL domains identified herein that bind to CD79b can be engineered into a Fab, F(ab')2, Fd, or Fv format and their binding to CD79b can be assessed using the assays described herein.

[0196] In some embodiments, the Fab comprises heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131.

[0197] In some embodiments, the Fab comprises an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132.

[0198] In some embodiments, the Fab comprises an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0199] In some embodiments, the Fab comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131; an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132; and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0200] In some embodiments, the Fab HCDR1, HCDR2, and HCDR3 of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:101, SEQ ID NO:102, and SEQ ID NO:103, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:121, SEQ ID NO:122, and SEQ ID NO:123, respectively; or Each comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO:131, SEQ ID NO:132, and SEQ ID NO:133, respectively.

[0201] In some embodiments, the Fab comprises light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134.

[0202] In some embodiments, the Fab comprises an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135.

[0203] In some embodiments, the Fab comprises an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0204] In some embodiments, the Fab comprises an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0205] In some embodiments, the Fab LCDR, LCDR2, and LCDR3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; the LCDR, LCDR2, and LCDR3 of SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or They comprise the LCDR, LCDR2, and LCDR3 of SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0206] In some embodiments, the Fab comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131, an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132, and an HCDR2 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133. and an HCDR3 and an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0207] In some embodiments, the Fab is HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0208] In some embodiments, the Fab comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137.

[0209] In some embodiments, the Fab comprises a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0210] In some embodiments, the Fab comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0211] In some embodiments, the Fab is VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or They comprise the VH and VL of SEQ ID NO: 137 and SEQ ID NO: 138, respectively.

[0212] In some embodiments, the F(ab')2 comprises heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131.

[0213] In some embodiments, the F(ab')2 comprises HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132.

[0214] In some embodiments, the F(ab')2 comprises an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0215] In some embodiments, the F(ab')2 comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131; an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132; and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0216] In some embodiments, the F(ab')2 is HCDR1, HCDR2, and HCDR3 of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:101, SEQ ID NO:102, and SEQ ID NO:103, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:121, SEQ ID NO:122, and SEQ ID NO:123, respectively; or Each comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO:131, SEQ ID NO:132, and SEQ ID NO:133, respectively.

[0217] In some embodiments, the F(ab')2 comprises light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134.

[0218] In some embodiments, the F(ab')2 comprises an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135.

[0219] In some embodiments, the F(ab')2 comprises an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0220] In some embodiments, the F(ab')2 comprises an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0221] In some embodiments, the F(ab')2 is LCDR, LCDR2, and LCDR3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; the LCDR, LCDR2, and LCDR3 of SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or They comprise the LCDR, LCDR2, and LCDR3 of SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0222] In some embodiments, the F(ab')2 comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131, an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132, and an HCDR2 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:13. 3, an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124 or SEQ ID NO:134, an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125 or SEQ ID NO:135, and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126 or SEQ ID NO:136.

[0223] In some embodiments, the F(ab')2 is HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0224] In some embodiments, the F(ab')2 comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137.

[0225] In some embodiments, the F(ab')2 comprises a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0226] In some embodiments, the F(ab')2 comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0227] In some embodiments, the F(ab')2 is VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or They comprise the VH and VL of SEQ ID NO: 137 and SEQ ID NO: 138, respectively.

[0228] In some embodiments, the Fv comprises heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131.

[0229] In some embodiments, the Fv comprises HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132.

[0230] In some embodiments, the Fv comprises an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0231] In some embodiments, the Fv comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131; an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132; and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0232] In some embodiments, the Fv HCDR1, HCDR2, and HCDR3 of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:101, SEQ ID NO:102, and SEQ ID NO:103, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:121, SEQ ID NO:122, and SEQ ID NO:123, respectively; or Each comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO:131, SEQ ID NO:132, and SEQ ID NO:133, respectively.

[0233] In some embodiments, the Fv comprises light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134.

[0234] In some embodiments, the Fv comprises an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135.

[0235] In some embodiments, the Fv comprises an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0236] In some embodiments, the Fv comprises an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0237] In some embodiments, the Fv comprises: LCDR, LCDR2, and LCDR3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; the LCDR, LCDR2, and LCDR3 of SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or They comprise the LCDR, LCDR2, and LCDR3 of SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0238] In some embodiments, the Fv comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131, an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132, and an H of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133. and a CDR3 and an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; a LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and a LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0239] In some embodiments, the Fv comprises: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0240] In some embodiments, the Fv comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137.

[0241] In some embodiments, the Fv comprises a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0242] In some embodiments, the Fv comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0243] In some embodiments, the Fv comprises: VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or They comprise the VH and VL of SEQ ID NO: 137 and SEQ ID NO: 138, respectively.

[0244] Homologous antigen-binding domains and antigen-binding domains with conservative substitutions Variants of the antigen binding domain that binds CD79b are within the scope of the present disclosure. For example, the variants may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 or more amino acid substitutions in the antigen binding domain that binds CD79b, so long as the variant retains or has improved functional properties when compared to the parent antigen binding domain. In some embodiments, the sequence identity may be about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% relative to the antigen binding domain that binds CD79b of the present disclosure. In some embodiments, the diversity is in the framework regions, hi some embodiments, the variants are generated by conservative substitutions.

[0245] In some embodiments, the antigen binding domain that binds CD79b comprises an HCDR1 that is at least 80% identical to the HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131. In some embodiments, the identity is at least 85%. In some embodiments, the identity is at least 90%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 92%. In some embodiments, the identity is at least 93%. In some embodiments, the identity is at least 94%. In some embodiments, the identity is at least 95%. In some embodiments, the identity is at least 96%. In some embodiments, the identity is at least 97%. In some embodiments, the identity is at least 98%. In some embodiments, the identity is at least 99%.

[0246] In some embodiments, the antigen binding domain that binds CD79b comprises an HCDR2 that is at least 80% identical to the HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132. In some embodiments, the identity is at least 85%. In some embodiments, the identity is at least 90%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 92%. In some embodiments, the identity is at least 93%. In some embodiments, the identity is at least 94%. In some embodiments, the identity is at least 95%. In some embodiments, the identity is at least 96%. In some embodiments, the identity is at least 97%. In some embodiments, the identity is at least 98%. In some embodiments, the identity is at least 99%.

[0247] In some embodiments, the antigen binding domain that binds CD79b comprises an HCDR3 that is at least 80% identical to the HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133. In some embodiments, the identity is at least 85%. In some embodiments, the identity is at least 90%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 92%. In some embodiments, the identity is at least 93%. In some embodiments, the identity is at least 94%. In some embodiments, the identity is at least 95%. In some embodiments, the identity is at least 96%. In some embodiments, the identity is at least 97%. In some embodiments, the identity is at least 98%. In some embodiments, the identity is at least 99%.

[0248] In some embodiments, the antigen binding domain that binds CD79b comprises an LCDR1 that is at least 80% identical to the LCDR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134. In some embodiments, the identity is at least 85%. In some embodiments, the identity is at least 90%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 92%. In some embodiments, the identity is at least 93%. In some embodiments, the identity is at least 94%. In some embodiments, the identity is at least 95%. In some embodiments, the identity is at least 96%. In some embodiments, the identity is at least 97%. In some embodiments, the identity is at least 98%. In some embodiments, the identity is at least 99%.

[0249] In some embodiments, the antigen binding domain that binds CD79b comprises an LCDR2 that is at least 80% identical to the LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135. In some embodiments, the identity is at least 85%. In some embodiments, the identity is at least 90%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 92%. In some embodiments, the identity is at least 93%. In some embodiments, the identity is at least 94%. In some embodiments, the identity is at least 95%. In some embodiments, the identity is at least 96%. In some embodiments, the identity is at least 97%. In some embodiments, the identity is at least 98%. In some embodiments, the identity is at least 99%.

[0250] In some embodiments, the antigen binding domain that binds CD79b comprises an LCDR3 that is at least 80% identical to the LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136. In some embodiments, the identity is at least 85%. In some embodiments, the identity is at least 90%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 92%. In some embodiments, the identity is at least 93%. In some embodiments, the identity is at least 94%. In some embodiments, the identity is at least 95%. In some embodiments, the identity is at least 96%. In some embodiments, the identity is at least 97%. In some embodiments, the identity is at least 98%. In some embodiments, the identity is at least 99%.

[0251] Also, VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or Also provided is an antigen-binding domain that binds CD79b comprising a VH and VL that are at least 80% identical to the VH and VL of SEQ ID NO:137 and SEQ ID NO:138, respectively.

[0252] In some embodiments, the identity is at least 85%. In some embodiments, the identity is at least 90%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 91%. In some embodiments, the identity is at least 92%. In some embodiments, the identity is at least 93%. In some embodiments, the identity is at least 94%. In some embodiments, the identity is at least 95%. In some embodiments, the identity is at least 96%. In some embodiments, the identity is at least 97%. In some embodiments, the identity is at least 98%. In some embodiments, the identity is at least 99%.

[0253] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions x 100), taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each gap.

[0254] The percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput Appl Biosci 4:11-17 (1988)) as incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can also be determined using the algorithm of Needleman and Wunsch (J Mol Biol 48:444-453 (1970)) as incorporated into the GAP program of the GCG software package (available at www_gcg_com) using either a Blossum 62 matrix or a PAM250 matrix, gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6.

[0255] In some embodiments, a variant of an antigen binding domain that binds CD79b contains one or two conservative substitutions in any of the CDR regions while retaining the desired functional property of the parent antigen binding fragment that binds CD79b.

[0256] "Conservative modifications" refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid modification. Conservative modifications include amino acid substitutions, additions, and deletions. A conservative amino acid substitution is one in which an amino acid is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are well defined and include amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), basic side chains (e.g., lysine, arginine, histidine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), uncharged polar side chains (e.g., glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine, tryptophan), aromatic side chains (e.g., phenylalanine, tryptophan, histidine, tyrosine), aliphatic side chains (e.g., glycine, alanine, valine, leucine, isoleucine, serine, threonine), amides (e.g., asparagine, glutamine), beta-branched side chains (e.g., threonine, valine, isoleucine), and sulfur-containing side chains (cysteine, methionine). Additionally, any naturally occurring residue in the polypeptide may also be substituted with alanine, as previously described for alanine scanning mutagenesis (MacLennan et al., (1988) Acta Physiol Scand Suppl 643:55-67; ​​Sasaki et al., (1988) Adv Biophys 35:1-24). Amino acid substitutions to the antibodies of the invention can be made by known methods, such as PCR mutagenesis (U.S. Pat. No. 4,683,195). Alternatively, libraries of variants can be generated using, for example, random codons (NNK) or non-random codons, such as the DVK codons that code for 11 amino acids (Ala, Cys, Asp, Glu, Gly, Lys, Asn, Arg, Ser, Tyr, Trp). The resulting variants can be tested for their characteristics using the assays described herein.

[0257] Methods for producing antigen-binding fragments that bind to CD79b The antigen-binding domains that bind to CD79b provided in the present disclosure can be produced using various techniques. For example, the hybridoma method of Kohler and Milstein can be used to identify VH / VL pairs that bind to CD79b. In the hybridoma method, mice or other host animals, such as hamsters, rats, or chickens, are immunized with human and / or cynomolgus CD79b, and then spleen cells of the immunized animals are fused with myeloma cells using standard methods to form hybridoma cells. Colonies arising from a single immortalized hybridoma cell can be screened for the production of antibodies containing an antigen-binding domain that binds to CD79b with desired properties, such as binding specificity, cross-reactivity or lack thereof, affinity for antigen, and any desired functionality.

[0258] The antigen-binding domain that binds to CD79b produced by immunizing a non-human animal may be humanized. Exemplary humanization techniques that involve the selection of a human acceptor framework include CDR grafting (US Pat. No. 5,225,539), SDR grafting (US Pat. No. 6,818,749), resurfacing (Padlan, (1991) Mol Immunol 28:489-499), specificity determining residue resurfacing (US Patent Application Publication No. 2010 / 0261620), human framework adaptation (US Pat. No. 8,748,356), or superhumanization (US Pat. No. 7,709,226). In these methods, the CDRs or a subset of CDR residues of a parent antibody are grafted onto a human framework that may be selected based on overall homology to the parent framework, based on similarity in CDR length or identity of canonical structure, or a combination thereof.

[0259] The humanized antigen-binding domain may be further optimized to improve its selectivity or affinity for the desired antigen, by techniques such as those described in WO 1990 / 007861 and WO 1992 / 22653, by incorporating altered framework support residues to retain binding affinity (backmutation), or by introducing diversity into any of the CDRs, e.g. to improve the affinity of the antigen-binding domain.

[0260] Transgenic animals, such as mice, rats, or chickens carrying human immunoglobulin (Ig) loci in their genome, can be used to generate antigen-binding fragments that bind CD79b, as described, for example, in U.S. Patent No. 6,150,584, WO 1999 / 45962, WO 2002 / 066630, WO 2002 / 43478, WO 2002 / 043478, and WO 1990 / 04036. The endogenous immunoglobulin loci of such animals can be disrupted or deleted, and at least one complete or partial human immunoglobulin locus can be inserted into the animal's genome using homologous or non-homologous recombination, using a transchromosome, or using a minigene. Companies such as Regeneron (www_regeneron_com), Harbour Antibodies (www_harbourantibodies_com), Open Monoclonal Technology, Inc. (OMT) (www_omtinc_net), KyMab (www_kymab_com), Trianni (www_trianni_com), and Ablexis (www_ablexis_com) may be involved in providing human antibodies against a selected antigen using the above technology.

[0261] Antigen binding domains that bind to CD79b can be selected from phage display libraries in which phage have been engineered to express human immunoglobulins or portions thereof, such as Fabs, single chain antibodies (scFvs), or unpaired or paired antibody variable regions. Antigen binding domains that bind to CD79b can be isolated from phage display libraries expressing antibody heavy and light chain variable regions as fusion proteins with bacteriophage pIX coat protein, for example, as described in Shi et al., (2010) J Mol Biol 397:385-96, and WO 09 / 085462). Libraries can be screened for phage binding to human and / or cynomolgus CD79b, and the resulting positive clones can be further characterized and Fabs isolated from clonal lysates and converted to scFvs or other configurations of antigen binding fragments.

[0262] Preparation of immunogenic antigens and expression and production of antigen binding domains of the present disclosure can be performed using any suitable technique, such as recombinant protein production. Immunogenic antigens may be administered to an animal in the form of purified proteins or protein mixtures including whole cells or cell or tissue extracts, or the antigens may be formed de novo in the animal from nucleic acids encoding the antigen or a portion thereof.

[0263] Conjugation to half-life extending moieties The antigen binding domain that binds to CD79b of the present disclosure may be conjugated to a half-life extending moiety. Exemplary half-life extending moieties are albumin, albumin variants, albumin binding proteins and / or domains, transferrin and fragments and analogs thereof, immunoglobulins (Ig) or fragments thereof, such as Fc regions. The amino acid sequences of the aforementioned half-life extending moieties are known. Ig or fragments thereof include all isotypes, i.e., IgG1, IgG2, IgG3, IgG4, IgM, IgA, and IgE.

[0264] Additional half-life extending moieties that may be conjugated to the antigen binding domain that binds CD79b of the present disclosure include polyethylene glycol (PEG) molecules, e.g., PEG5000 or PEG20,000, fatty acids and fatty acid esters of different chain lengths, e.g., laurate, myristic acid, stearate, arachidic acid, behenic acid, oleic acid, arachidonic acid, octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, etc., polylysine, octane, carbohydrates (dextran, cellulose, oligosaccharides or polysaccharides) for desired properties. These moieties may be fused directly to the antigen binding domain that binds CD79b of the present disclosure or may be produced by standard cloning and expression techniques. Alternatively, the moieties may be attached to recombinantly produced antigen binding domains that bind CD79b of the present disclosure using well-known chemical coupling methods.

[0265] For example, a pegylated moiety can be conjugated to an antigen binding domain that binds CD79b of the present disclosure by incorporating a cysteine ​​residue at the C-terminus of the antigen binding domain that binds CD79b of the present disclosure or engineering a cysteine ​​into a residue position that faces away from the CD79b binding site and attaching the pegyl group to the cysteine ​​using well-known methods.

[0266] In some embodiments, the antigen-binding fragment that binds CD79b is conjugated to a half-life extending moiety.

[0267] In some embodiments, the half-life extending moiety is an immunoglobulin (Ig), a fragment of Ig, an Ig constant region, a fragment of an Ig constant region, an Fc region, transferrin, albumin, an albumin binding domain, or polyethylene glycol. In some embodiments, the half-life extending moiety is an Ig constant region.

[0268] In some embodiments, the half-life extending moiety is Ig.

[0269] In some embodiments, the half-life extending moiety is a fragment of Ig.

[0270] In some embodiments, the half-life extending moiety is an Ig constant region.

[0271] In some embodiments, the half-life extending moiety is a fragment of an Ig constant region.

[0272] In some embodiments, the half-life extending moiety is an Fc region.

[0273] In some embodiments, the half-life extending moiety is albumin.

[0274] In some embodiments, the half-life extending moiety is an albumin binding domain.

[0275] In some embodiments, the half-life extending moiety is transferrin.

[0276] In some embodiments, the half-life extending moiety is polyethylene glycol.

[0277] Antigen binding domains that bind CD79b conjugated to half-life extending moieties can be evaluated for their pharmacokinetic properties using known in vivo models.

[0278] Isotype, allotype, and Fc engineering The Ig constant region or fragment of an Ig constant region, such as an Fc region, present in the proteins of the disclosure may be of any allotype or isotype.

[0279] In some embodiments, the Ig constant region or fragment of an Ig constant region is of the IgG1 isotype.

[0280] In some embodiments, the Ig constant region or fragment of an Ig constant region is an IgG2 isotype.

[0281] In some embodiments, the Ig constant region or fragment of an Ig constant region is of the IgG3 isotype.

[0282] In some embodiments, the Ig constant region or fragment of an Ig constant region is of the IgG4 isotype.

[0283] The Ig constant region or a fragment of the Ig constant region can be of any allotype. The allotype is not expected to affect the properties of the Ig constant region, such as binding or Fc-mediated effector functions. The immunogenicity of therapeutic proteins containing fragment Ig constant regions is associated with an increased risk of infusion reactions and a shorter duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which therapeutic proteins containing fragment Ig constant regions induce an immune response in the host may be determined in part by the allotype of the Ig constant region (Stickler et al., (2011) Genes and Immunity 12:213-21). The allotype of the Ig constant region is related to the variation of the amino acid sequence at a specific position in the constant region sequence of the antibody. Table 1 shows selected IgG1, IgG2, and IgG4 allotypes.

[0284] [Table 1]

[0285] C-terminal lysine (CTL) can be removed from Ig constant regions by endogenous circulating carboxypeptidases in the bloodstream (Cai et al., (2011) Biotechnol Bioeng 108:404-412). During production, extracellular Zn was removed as described in US Patent Application Publication No. 2014 / 0273092. 2+ , EDTA, or EDTA-Fe 3+ By controlling the concentration of, the removal of CTL can be controlled to less than maximal levels. The CTL content of the protein can be measured using known methods.

[0286] In some embodiments, the antigen-binding fragment that binds to CD79b conjugated to an Ig constant region has a C-terminal lysine content of about 10% to about 90%. In some embodiments, the C-terminal lysine content is about 20% to about 80%. In some embodiments, the C-terminal lysine content is about 40% to about 70%. In some embodiments, the C-terminal lysine content is about 55% to about 70%. In some embodiments, the C-terminal lysine content is about 60%.

[0287] Fc region mutations can be made to an antigen binding domain that binds CD79b conjugated to an Ig constant region or a fragment of an Ig constant region to modulate effector functions such as ADCC, ADCP, and / or ADCP, and / or pharmacokinetic properties. This can be achieved by introducing mutations in the Fc that control binding of the mutated Fc to activating FcγRs (FcγRI, FcγRIIa, FcγRIII), FcγRIIb, and / or FcRn.

[0288] In some embodiments, the antigen binding domain that binds CD79b conjugated to an Ig constant region or a fragment of an Ig constant region comprises at least one mutation in the Ig constant region or a fragment of an Ig constant region.

[0289] In some embodiments, at least one mutation is in the Fc region.

[0290] In some embodiments, the antigen binding domain that binds CD79b conjugated to an Ig constant region or a fragment of an Ig constant region comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mutations in the Fc region.

[0291] In some embodiments, the antigen binding domain that binds CD79b conjugated to an Ig constant region, or a fragment of an Ig constant region, comprises at least one mutation in the Fc region that modulates binding of the antibody to FcRn.

[0292] Positions in Fc that can be mutated to modulate half-life (e.g., binding to FcRn) include positions 250, 252, 253, 254, 256, 257, 307, 376, 380, 428, 434, and 435. Exemplary mutations that can be made alone or in combination are the mutations T250Q, M252Y, I253A, S254T, T256E, P257I, T307A, D376V, E380A, M428L, H433K, N434S, N434A, N434H, N434F, H435A, and H435R. Exemplary mutations that may be made, either alone or in combination, to increase the half-life of an antibody are the mutations M428L / N434S, M252Y / S254T / T256E, T250Q / M428L, N434A, and T307A / E380A / N434A. Exemplary mutations that may be made, either alone or in combination, to decrease the half-life are the mutations H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E / H433K / N434F, T308P / N434A, and H435R.

[0293] In some embodiments, the antigen binding domain that binds CD79b conjugated to an Ig constant region or a fragment of an Ig constant region comprises M252Y / S254T / T256E mutations.

[0294] In some embodiments, the antigen binding domain that binds CD79b conjugated to an Ig constant region or a fragment of an Ig constant region comprises at least one mutation in the Fc region that enhances binding of the protein to Fcγ receptors (FcγR) and / or reduces an Fc effector function, such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and / or phagocytosis (ADCP).

[0295] Fc positions that may be mutated to reduce binding of the protein to activating FcγRs and subsequently reduce effector function include positions 214, 233, 234, 235, 236, 237, 238, 265, 267, 268, 270, 295, 297, 309, 327, 328, 329, 330, 331, and 365. Exemplary mutations that can be made alone or in combination are the mutations K214T, E233P, L234V, L234A, deletion of G236, V234A, F234A, L235A, G237A, P238A, P238S, D265A, S267E, H268A, H268Q, Q268A, N297A, A327Q, P329A, D270A, Q295A, V309L, A327S, L328F, A330S, and P331S in IgG1, IgG2, IgG3, or IgG4. Exemplary combinations of mutations that result in proteins with reduced ADCC are L234A / L235A in IgG1, L234A / L235A / D265S in IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S in IgG2, F234A / L235A in IgG4, S228P / F234A / L235A in IgG4, N297A in all Ig isotypes, V234A / G237A in IgG2, K214T / E233P / L234V / L235A / G in IgG1 ... These mutations are 236 deletion / A327G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S in IgG2, S267E / L328F in IgG1, L234F / L235E / D265A in IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S in IgG1, S228P / F234A / L235A / G237A / P238S in IgG4, and S228P / F234A / L235A / G236 deletion / G237A / P238S in IgG4. A hybrid IgG2 / 4 Fc domain may also be used, such as an Fc having residues 117-260 from IgG2 and residues 261-447 from IgG4.

[0296] An exemplary mutation that results in a protein with reduced CDC is the K322A mutation.

[0297] The well-known S228P mutation can be added to IgG4 antibodies to enhance the stability of IgG4.

[0298] In some embodiments, the antigen binding domain that binds CD79b conjugated to an Ig constant region or a fragment of an Ig constant region comprises at least one mutation selected from the group consisting of K214T, E233P, L234V, L234A, deletion of G236, V234A, F234A, L235A, G237A, P238A, P238S, D265A, S267E, H268A, H268Q, Q268A, N297A, A327Q, P329A, D270A, Q295A, V309L, A327S, L328F, K322, A330S, and P331S.

[0299] In some embodiments, the antigen binding domain that binds CD79b conjugated to an Ig constant region or a fragment of an Ig constant region comprises L234A / L235A / D265S mutations.

[0300] In some embodiments, the antigen binding domain that binds to CD79b conjugated to an Ig constant region or a fragment of an Ig constant region comprises L234A / L235A mutations.

[0301] In some embodiments, the antigen binding domain that binds CD79b conjugated to an Ig constant region, or a fragment of an Ig constant region, comprises at least one mutation in the Fc region that enhances binding of the protein to Fcγ receptors (FcγR) and / or enhances an Fc effector function, such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and / or phagocytosis (ADCP).

[0302] Fc positions that can be mutated to increase binding of the protein to activating FcγR and / or enhance Fc effector function include positions 236, 239, 243, 256, 290, 292, 298, 300, 305, 312, 326, 330, 332, 333, 334, 345, 360, 339, 378, 396, or 430 (residue numbering according to the EU index). Exemplary mutations that can be made singly or in combination are G236A, S239D, F243L, T256A, K290A, R292P, S298A, Y300L, V305L, K326A, A330K, I332E, E333A, K334A, A339T, and P396L. Exemplary combinations of mutations that result in proteins with increased ADCC or ADCP are S239D / I332E, S298A / E333A / K334A, F243L / R292P / Y300L, F243L / R292P / Y300L / P396L, F243L / R292P / Y300L / V305I / P396L, and G236A / S239D / I332E.

[0303] Fc positions that may be mutated to enhance CDC include positions 267, 268, 324, 326, 333, 345, and 430. Exemplary mutations that may be made singly or in combination are S267E, F1268F, S324T, K326A, K326W, E333A, E345K, E345Q, E345R, E345Y, E430S, E430F, and E430T. Exemplary combination mutations that result in proteins with increased CDC are K326A / E333A, K326W / E333A, H268F / S324T, S267E / H268F, S267E / S324T, and S267E / H268F / S324T.

[0304] The specific mutations described herein are mutations compared to the wild-type amino acid sequences of IgG1, IgG2, and IgG4 of SEQ ID NOs: 174, 175, and 176, respectively.

[0305] SEQ ID NO:174 - Wild type IgG1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0306] SEQ ID NO:175 - Wild type IgG2 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKDTLMISRTPEVTCVVDVSHEDPEVQFNWYVDGVEV HNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0307] SEQ ID NO:176 - Wild type IgG4 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0308] Binding of antibodies to FcγR or FcRn can be assessed using flow cytometry in cells engineered to express the respective receptor. In an exemplary binding assay, 2×10 5Cells are seeded at 1 / well and blocked in BSA Stain Buffer (BD Biosciences, San Jose, USA) for 30 min at 4°C. Cells are incubated with test antibodies on ice for 1.5 h at 4°C. After washing twice with BSA stain buffer, cells are incubated with R-PE-labeled anti-human IgG secondary antibody (Jackson Immunoresearch Laboratories) for 45 min at 4°C. Cells are washed twice with stain buffer and then resuspended in 150 μL of Stain Buffer containing 1:200 diluted DRAQ7 Live / Dead Cell Stain Reagent (Cell Signaling Technology, Danvers, USA). PE and DRAQ7 signals of stained cells are detected by Miltenyi MACSQuant flow cytometer (Miltenyi Biotec, Auburn, USA) using B2 and B4 channels, respectively. Live cells are gated with DRAQ7 exclusion and the geometric mean fluorescent signal is determined for at least 10,000 live cell events collected. FlowJo software (Tree Star) is used for analysis. Data are plotted as the logarithm of the antibody concentration versus the mean fluorescent signal. Nonlinear regression analysis is performed.

[0309] A protein comprising an antigen-binding domain that binds to CD79b of the present disclosure The antigen binding domains that bind CD79b of the present disclosure can be engineered into monospecific or multispecific proteins of various designs using standard methods. The present disclosure also provides monospecific proteins comprising an isolated antigen binding domain that binds CD79b of the present disclosure. In some embodiments, the monospecific protein is an antibody.

[0310] Generally, without being limited to this approach, when constructing antibodies as multispecific antibodies, a binding domain module (first, second, third, etc.) for each target is optionally constructed from an scFv, Fab, Fab', F(ab')2, Fv, variable domain (e.g., VH or VL), diabody, minibody or full-length antibody. For example, each such binding domain or module is made in one or more of the following non-limiting formats, where binding domains comprising variable domains, and / or full-length antibodies, and / or antibody fragments are operably linked in tandem to generate the multispecific antibody:

[0311] In one embodiment, a multispecific antibody is provided comprising at least one first antibody-derived binding domain targeting CD79b operably linked to at least one second antibody binding domain targeting a second epitope. Optionally, the binding domains comprise at least one or more VH and cognate VL binding domains, or one or more VH-CH1-CH2-CH2 and cognate VL-CL binding domains, or one or more antibody fragment binding domains.

[0312] The present disclosure also provides a multispecific protein comprising an antigen-binding domain that binds to CD79b of the present disclosure.

[0313] In some embodiments, the multispecific protein is bispecific.

[0314] In some embodiments, the multispecific protein is trispecific.

[0315] In some embodiments, the multispecific protein is tetraspecific.

[0316] In some embodiments, the multispecific protein is monovalent for binding to CD79b.

[0317] In some embodiments, the multispecific protein is bivalent for binding to CD79b.

[0318] The present disclosure also provides an isolated multispecific protein comprising a first antigen-binding domain that binds CD79b and a second antigen-binding domain that binds a second antigen, in some embodiments, the first antigen-binding domain that binds CD79b and / or the second antigen-binding domain that binds a second antigen comprises an scFv, (scFv)2, Fv, Fab, F(ab')2, Fd, dAb, or VHH.

[0319] In some embodiments, the first antigen binding domain that binds CD79b and / or the second antigen binding domain that binds a second antigen comprises a Fab.

[0320] In some embodiments, the first antigen binding domain that binds CD79b and / or the second antigen binding domain that binds a second antigen comprises F(ab')2.

[0321] In some embodiments, the first antigen binding domain that binds CD79b and / or the second antigen binding domain that binds a second antigen comprises a VHH.

[0322] In some embodiments, the first antigen binding domain that binds CD79b and / or the second antigen binding domain that binds a second antigen comprises an Fv.

[0323] In some embodiments, the first antigen binding domain that binds CD79b and / or the second antigen binding domain that binds a second antigen comprises an Fd.

[0324] In some embodiments, the first antigen binding domain that binds CD79b and / or the second antigen binding domain that binds a second antigen comprises an scFv.

[0325] In some embodiments, the scFv comprises, from N-terminus to C-terminus, a VH, a first linker (L1), and a VL (VH-L1-VL), or a VL, L1, and VH (VL-L1-VH). In some embodiments, L1 comprises about 5-50 amino acids. In some embodiments, L1 comprises about 5-40 amino acids. In some embodiments, L1 comprises about 10-30 amino acids. In some embodiments, L1 comprises about 10-20 amino acids. In some embodiments, L1 comprises the amino acid sequence of SEQ ID NOs: 141-173.

[0326] In some embodiments, the first antigen binding domain that binds to CD79b comprises HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131.

[0327] In some embodiments, the first antigen binding domain that binds to CD79b comprises the HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132.

[0328] In some embodiments, the first antigen binding domain that binds to CD79b comprises the HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0329] In some embodiments, the first antigen binding domain that binds CD79b comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131; an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132; and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0330] In some embodiments, the first antigen binding domain that binds to CD79b is HCDR1, HCDR2, and HCDR3 of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:101, SEQ ID NO:102, and SEQ ID NO:103, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:121, SEQ ID NO:122, and SEQ ID NO:123, respectively; or Each comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO:131, SEQ ID NO:132, and SEQ ID NO:133, respectively.

[0331] In some embodiments, the first antigen binding domain that binds to CD79b comprises light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134.

[0332] In some embodiments, the first antigen binding domain that binds to CD79b comprises an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135.

[0333] In some embodiments, the first antigen binding domain that binds to CD79b comprises an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0334] In some embodiments, the first antigen binding domain that binds CD79b comprises an LCDR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0335] In some embodiments, the first antigen binding domain that binds to CD79b is LCDR, LCDR2, and LCDR3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; the LCDR, LCDR2, and LCDR3 of SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or They comprise the LCDR, LCDR2, and LCDR3 of SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0336] In some embodiments, the first antigen binding domain that binds CD79b comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131, an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132, and an HCDR2 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or comprises an HCDR3 of SEQ ID NO:133, an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124 or SEQ ID NO:134, an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125 or SEQ ID NO:135, and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126 or SEQ ID NO:136.

[0337] In some embodiments, the first antigen binding domain that binds to CD79b is HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0338] In some embodiments, the first antigen binding domain that binds to CD79b comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137.

[0339] In some embodiments, the first antigen binding domain that binds to CD79b comprises a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0340] In some embodiments, the first antigen-binding domain that binds CD79b comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0341] In some embodiments, the first antigen binding domain that binds to CD79b is VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or They comprise the VH and VL of SEQ ID NO: 137 and SEQ ID NO: 138, respectively.

[0342] In some embodiments, a first antigen-binding domain that binds CD79b is conjugated to a first immunoglobulin (Ig) constant region or a fragment of a first Ig constant region, and / or a second antigen-binding domain that binds a second antigen is conjugated to a second immunoglobulin (Ig) constant region or a fragment of a second Ig constant region.

[0343] In some embodiments, the first Ig constant region fragment and / or the second Ig constant region fragment comprises an Fc region.

[0344] In some embodiments, the first Ig constant region fragment and / or the second Ig constant region fragment comprises a CH2 domain.

[0345] In some embodiments, the first Ig constant region fragment and / or the second Ig constant region fragment comprises a CH3 domain.

[0346] In some embodiments, the first Ig constant region fragment and / or the second Ig constant region fragment comprises a CH2 domain and a CH3 domain.

[0347] In some embodiments, the first Ig constant region fragment and / or the second Ig constant region fragment comprises at least a portion of the hinge, the CH2 domain, and the CH3 domain.

[0348] In some embodiments, the fragment of an Ig constant region includes a hinge, a CH2 domain, and a CH3 domain.

[0349] In some embodiments, the multispecific protein further comprises a second linker (L2) between the first antigen binding domain that binds CD79b and the first Ig constant region or fragment of the first Ig constant region, and between the second antigen binding domain that binds the second antigen and the second Ig constant region or fragment of the second Ig constant region.

[0350] In some embodiments, L2 comprises the amino acid sequence of SEQ ID NO:141 to SEQ ID NO:173.

[0351] In some embodiments, the first Ig constant region or fragment of a first Ig constant region and the second Ig constant region or fragment of a second Ig constant region are of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0352] In some embodiments, the first Ig constant region or fragment of a first Ig constant region and the second Ig constant region or fragment of a second Ig constant region are of the IgG1 isotype.

[0353] In some embodiments, the first Ig constant region or fragment of a first Ig constant region and the second Ig constant region or fragment of a second Ig constant region are of the IgG2 isotype.

[0354] In some embodiments, the first Ig constant region or fragment of a first Ig constant region and the second Ig constant region or fragment of a second Ig constant region are of the IgG3 isotype.

[0355] In some embodiments, the first Ig constant region or fragment of a first Ig constant region and the second Ig constant region or fragment of a second Ig constant region are of the IgG4 isotype.

[0356] The first Ig constant region or fragment of a first Ig constant region and the second Ig constant region or fragment of a second Ig constant region may be further engineered as described herein.

[0357] In some embodiments, the first Ig constant region or fragment of a first Ig constant region and the second Ig constant region or fragment of a second Ig constant region comprise at least one mutation that results in reduced binding of the multispecific protein to an FcγR.

[0358] In some embodiments, the at least one mutation that results in reduced binding of the multispecific protein to an FcγR is selected from the group consisting of F234A / L235A, L234A / L235A, L234A / L235A / D265S, V234A / G237A / P238S / H268A / V309L / A330S / P331S, F234A / L235A, S228P / F234A / L235A, N297A, V234A / G237A, K214T / E233P / L234V / L235A / G236 deletion / A330S / P331S. 27G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S, S267E / L328F, L234F / L235E / D265A, L234A / L235A / G237A / P238S / H268A / A330S / P331S, S228P / F234A / L235A / G237A / P238S, and S228P / F234A / L235A / G236 deletion / G237A / P238S, where residue numbering is according to the EU index.

[0359] In some embodiments, the first Ig constant region or fragment of a first Ig constant region and the second Ig constant region or fragment of a second Ig constant region comprise at least one mutation that results in enhanced binding of the multispecific protein to an Fcγ receptor (FcγR).

[0360] In some embodiments, the at least one mutation that results in enhanced binding of the multispecific protein to an FcγR is selected from the group consisting of S239D / I332E, S298A / E333A / K334A, F243L / R292P / Y300L, F243L / R292P / Y300L / P396L, F243L / R292P / Y300L / V305I / P396L, and G236A / S239D / I332E, where residue numbering is according to the EU index.

[0361] In some embodiments, the FcγR is FcγRI, FcγRIIA, FcγRIIB, or FcγRIII, or any combination thereof.

[0362] In some embodiments, the first Ig constant region or fragment of a first Ig constant region and the second Ig constant region or fragment of a second Ig constant region comprise at least one mutation that modulates the half-life of the multispecific protein.

[0363] In some embodiments, the at least one mutation that modulates the half-life of the multispecific protein is selected from the group consisting of H435A, P257I / N434H, D376V / N434H, M252Y / S254T / T256E / H433K / N434F, T308P / N434A, and H435R, where residue numbering is according to the EU index.

[0364] In some embodiments the multispecific protein comprises at least one mutation in the CH3 domain of a first Ig constant region or a fragment of a first Ig constant region and / or at least one mutation in the CH3 domain of a second Ig constant region or a fragment of a second Ig constant region.

[0365] In some embodiments, the at least one mutation in the CH3 domain of the first Ig constant region or the fragment of the first Ig constant region and / or the at least one mutation in the CH3 domain of the second Ig constant region or the fragment of the second Ig constant region is selected from the group consisting of T350V, L351Y, F405A, Y407V, T366Y, T366W, F405W, T394W, T394S, Y407T, Y407A, T366S / L368A / Y40 7V, L351Y / F405A / Y407V, T366I / K392M / T394W, F405A / Y407V, T366L / K392M / T394W, L351Y / Y407A, T366A / K409F, L351Y / Y407A, T366V / K409F, T366A / K409F, T350V / L351Y / F405A / Y407V, and T350V / T366L / K392L / T394W, where residue numbering is according to the EU index.

[0366] In some embodiments, the first Ig constant region or fragment of a first Ig constant region and the second Ig constant region or fragment of a second Ig constant region comprise the following mutations: L235A_L235A_D265S_T350V_L351Y_F405A_Y407V in the first Ig constant region and L235A_L235A_D265S_T350V_T366L_K392L_T394W in the second Ig constant region, or in the first Ig constant region, and L235A_L235A_D265S_T350V_T366L_K392L_T394W in the second Ig constant region.

[0367] Generation of multispecific proteins containing antigen-binding fragments that bind to CD79b The antigen-binding fragments that bind CD79b of the present disclosure may be engineered into multispecific antibodies, and such antibodies are also encompassed within the scope of the present invention.

[0368] Antigen-binding fragments that bind to CD79b may be engineered into full-length multispecific antibodies that are generated using Fab arm exchange, where substitutions are introduced into two monospecific bivalent antibodies in the Ig constant region CH3 domain that promote Fab arm exchange in vitro. In this method, two monospecific bivalent antibodies are engineered to have specific substitutions in the CH3 domain that promote the stability of the heterodimer. These antibodies are incubated together under reducing conditions sufficient to allow the cysteines in the hinge region to isomerize disulfide bonds, thereby generating bispecific antibodies by Fab arm exchange. The incubation conditions can be optimally returned to non-reducing conditions. Representative reducing agents that can be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol, preferably a reducing agent selected from the group consisting of 2-mercaptoethylamine, dithiothreitol, and tris(2-carboxyethyl)phosphine. For example, incubation at a temperature of at least 20° C., in the presence of at least 25 mM 2-MEA or in the presence of at least 0.5 mM dithiothreitol, at a pH of 5 to 8, for example pH 7.0 or pH 7.4, for at least 90 minutes can be used.

[0369] CH3 mutations that may be used include techniques such as knob-in-hole mutations (Genentech), electrostatic match mutations (Chugai, Amgen, NovoNordisk, Oncomed), Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), Duobody® mutations (Genmab), and other asymmetric mutations (e.g., Zymeworks).

[0370] Knob-in-hole mutations are disclosed, for example, in WO 1996 / 027011 and include mutations on the interface of the CH3 domains in which an amino acid with a small side chain (hole) is introduced into the first CH3 domain and an amino acid with a large side chain (knob) is introduced into the second CH3 domain, resulting in preferential interactions between the first and second CH3 domains. Exemplary CH3 domain mutations that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0371] Heavy chain heterodimer formation can be promoted using electrostatic interactions by substituting positively charged residues on the first CH3 region with negatively charged residues on the second CH3 region, as described in U.S. Patent Application Publication Nos. 2010 / 0015133, 2009 / 0182127, 2010 / 028637, or 2011 / 0123532.

[0372] Other asymmetric mutations that can be used to promote heavy chain heterodimerization include L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V ... 66L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0373] SEED body mutations involve replacing selected IgG residues with IgA residues to promote heavy chain heterodimerization, as described in US Patent Application Publication No. 20070287170.

[0374] Other exemplary mutations that may be used include R409D_K370E / D399K_E357K, S354C_T366W / Y349C_T366S_L368A_Y407V, Y349C_T366W / S354C_T366S_L368A_Y407V, and Y349C_T366W / S354C_T366S_L368A_Y407V, as described in WO 2007 / 147901, WO 2011 / 143545, WO 2013157954, WO 2013096291, and U.S. Patent Application Publication No. 2018 / 0118849. 8A_Y407V, T366K / L351D, L351K / Y349E, L351K / Y349D, L351K / L368E, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, K392D / D399K, K392D / E356K, K253E_D282K_K322D / D239K_E240K_K292D, K392D_K409D / D356K_D399K.

[0375] Duobody® mutations (Genmab) are described, for example, in U.S. Pat. No. 9,150,663 and U.S. Patent Publication No. 2014 / 0303356 and include the following mutations: F405L / K409R, wild type / F405L_R409K, T350I_K370T_F405L / K409R, K370W / K409R, D399AFGHILMNRSTVWY / K409R, T366ADEFGHILMQVY / K409R, L368ADEGHNRSTVQ / K409AGRH, D399FHKRQ / K409AGRH, F405IKLSTVW / K409AGRH, and Y407LWQ / K409AGRH.

[0376] Further bispecific or multispecific structures that may incorporate an antigen-binding domain that binds CD79b include Dual Variable Domain Immunoglobulins (DVDs) (WO 2009 / 134776; DVDs are full-length antibodies comprising a heavy chain with the structure VH1-linker-VH2-CH and a light chain with the structure VL1-linker-VL2-CL, with an optional linker), structures comprising various dimerization domains for linking two antibody arms with different specificities, e.g., leucine zippers or collagen dimerization domains (WO 2012 / 022811; U.S. Pat. Nos. 5,932,448, 6,833,441), two or more domain antibodies (dAbs) conjugated together, diabodies, heavy chain only antibodies such as camelid antibodies and genetically engineered camelid antibodies, Dual Targeting (DT)-Ig (GSK / Domantis), Two-in-one Antibody (Genentech), Cross-linked Mab (Karmanos Cancer Center), mAb2 (F-Star) and CovX-body (CovX / Pfizer), IgG-like Bispecific (InnClone / Eli Lilly), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc Fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion,Zymogenetics / BMS), Dual Affinity Retargeting Technology (Fc-DART) (MacroGenics), and Dual(ScFv)2-Fab (National Research Center for Antibody Medicine--China), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), Bivalent Bispecific (Biotecnol), and Fab-Fv (UCB-Celltech). ScFv antibodies, diabody-based antibodies, and domain antibodies include, but are not limited to, Bispecific T Cell Engager (BiTE) (Micromet), Tandem Diabody (Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (MacroGenics), single chain diabodies (Academic), TCR-like antibodies (AIT, ReceptorLogics), human serum albumin ScFv fusions (Merrimack), and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain only domain antibodies.

[0377] The antigen-binding domain that binds CD79b of the present disclosure may also be engineered into a multispecific protein comprising three polypeptide chains. In such designs, at least one antigen-binding domain is in the form of an scFv. Exemplary designs include the following designs 1-4 (where "1" denotes the first antigen-binding domain, "2" denotes the second antigen-binding domain, and "3" denotes the third antigen-binding domain): Design 1: Chain A) scFv1-CH2-CH3, Chain B) VL2-CL, Chain C) VH2-CH1-hinge-CH2-CH3 Design 2: Chain A) scFv1-hinge-CH2-CH3, Chain B) VL2-CL, Chain C) VH2-CH1-hinge-CH2-CH3 Design 3: Chain A) scFv1-CH1-hinge-CH2-CH3, Chain B) VL2-CL, Chain C) VH2-CH1-hinge-CH2-CH3 Design 4: Chain A) CH2-CH3-scFv1, Chain B) VL2-CL, Chain C) VH2-CH1-hinge-CH2-CH3 The CH3 operation may be performed using the L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, or T366L_K392M_T394W / F405A_Y407V described in U.S. Patent Application Publication No. 2012 / 0149876 or U.S. Patent Application Publication No. 2013 / 0195849 (Zymeworks). Mutations such as 407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W may be incorporated into Designs 1-4.

[0378] Conjugation to immunoglobulin (Ig) constant regions or fragments of Ig constant regions In some embodiments, the antigen binding domain that binds CD79b of the present disclosure can be conjugated to an Ig constant region or a fragment of an Ig constant region to confer antibody-like properties, including Fc effector functions C1q binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, or downregulation of cell surface receptors (e.g., B-cell receptors; BCR). The Ig constant region or a fragment of an Ig constant region can also function as a half-life extending moiety, as discussed herein. The antigen binding domain that binds CD79b of the present disclosure can be engineered into a conventional full-length antibody using standard methods. Full-length antibodies comprising an antigen binding domain that binds CD79b can be further engineered as described herein.

[0379] In some embodiments, the globulin heavy chain constant region consists of subdomains CH1, CH2 and CH3. In some embodiments, the CH1 domain spans residues A118-V215, the CH2 domain residues A231-K340, and the CH3 domain residues G341-K447 in the heavy chain, with residue numbering according to the EU index. In some instances, G341 is referred to as the CH2 domain residue. The hinge is generally defined to include E216 and terminate at P230 for human IgG1. In some embodiments, the Ig Fc region includes at least the CH2 and CH3 domains of the Ig constant region, and thus includes at least the region from about A231 to K447 of the Ig heavy chain constant region.

[0380] The present invention also provides an antigen-binding domain that binds CD79b conjugated to an immunoglobulin (Ig) constant region, or a fragment of an Ig constant region.

[0381] In some embodiments, the Ig constant region is a heavy chain constant region.

[0382] In some embodiments, the Ig constant region is a light chain constant region.

[0383] In some embodiments, the fragment of an Ig constant region comprises an Fc region.

[0384] In some embodiments, the fragment of an Ig constant region comprises a CH2 domain.

[0385] In some embodiments, the fragment of an Ig constant region comprises a CH3 domain.

[0386] In some embodiments, the fragment of an Ig constant region comprises a CH2 domain and a CH3 domain.

[0387] In some embodiments, the fragment of an Ig constant region comprises at least a portion of a hinge, a CH2 domain, and a CH3 domain. A portion of a hinge refers to one or more amino acid residues of an Ig hinge.

[0388] In some embodiments, the fragment of an Ig constant region includes a hinge, a CH2 domain, and a CH3 domain.

[0389] In some embodiments, the antigen binding domain that binds CD79b is conjugated to the N-terminus of an Ig constant region or a fragment of an Ig constant region.

[0390] In some embodiments, the antigen binding domain that binds CD79b is conjugated to the C-terminus of an Ig constant region or a fragment of an Ig constant region.

[0391] In some embodiments, the antigen binding domain that binds to CD79b is conjugated to the Ig constant region or a fragment of an Ig constant region via a second linker (L2).

[0392] In some embodiments, L2 comprises the amino acid sequence of SEQ ID NO:141 to SEQ ID NO:173.

[0393] The antigen binding domains that bind to CD79b of the present disclosure conjugated to an Ig constant region or a fragment of an Ig constant region can be assessed for their functionality using several known assays. Binding to CD79b can be assessed using the methods described herein. The altered properties conferred by an Ig constant domain or a fragment of an Ig constant region, e.g., an Fc region, can be assayed in an Fc receptor binding assay using a soluble form of a receptor, such as an FcγRI, FcγRII, FcγRIII, or FcRn receptor, or using a cell-based assay measuring, e.g., ADCC, CDC, or ADCP.

[0394] ADCC can be assessed using an in vitro assay using CD79b-expressing cells as target cells and NK cells as effector cells. Cytolysis can be detected by the release of a label (e.g., a radioactive substrate, a fluorescent dye, or a natural intracellular protein) from lysed cells. In an exemplary assay, target cells are used at a ratio of 1 target cell to 4 effector cells. Target cells are pre-labeled with BATDA and combined with effector cells and test antibodies. Cytolysis is measured by incubating samples for 2 hours and measuring the BATDA released into the supernatant. Data are normalized to maximum cytotoxicity with 0.67% Triton X-100 (Sigma Aldrich) and a minimum control is determined by the spontaneous release of BATDA from target cells in the absence of any antibody.

[0395] ADCP can be assessed by using monocyte-derived macrophages as effector cells and any CD79b-expressing cells genetically engineered to express GFP or other marker molecules as target cells. In an exemplary assay, the effector:target cell ratio can be, for example, 4:1. Effector cells can be incubated with target cells for 4 hours, with or without the addition of an antibody of the invention. After incubation, cells can be detached using activase. Macrophages can be identified using anti-CD11b and anti-CD14 antibodies conjugated to fluorescent labels, and the rate of phagocytosis can be measured using standard methods to measure CD11 + CD14 + It can be calculated based on the % GFP fluorescence in macrophages.

[0396] For CDC of cells, for example, Daudi cells were cultured at 1 × 10 5Lysing can be measured by seeding 100 cells / well (50 μL / well), adding 50 μL of test protein to the well at a final concentration of 0-100 μg / mL, incubating the reaction for 15 minutes at room temperature, adding 11 μL of pooled human serum to the well, and incubating the reaction for 45 minutes at 37° C. The percentage of lysed cells can be detected as the % of propidium iodide stained cells in a FACS assay using standard methods.

[0397] Glycogenetic Engineering The ability of the antigen-binding domain that binds to CD79b conjugated to an Ig constant region or a fragment of an Ig constant region to mediate ADCC can be enhanced by genetically engineering the oligosaccharide moiety of the Ig constant region or a fragment of an Ig constant region. Human IgG1 or IgG3 is N-glycosylated at Asn297, where the majority of the glycans are in the known biantennary G0, G0F, G1, G1F, G2, or G2F form. Ig constant region-containing proteins that can be produced by unengineered CHO cells typically have a glycan fucose content of at least about 85%. Removal of the core fucose from the biantennary complex type oligosaccharides attached to the antigen-binding domain that binds to CD79b conjugated to an Ig constant region or a fragment of an Ig constant region enhances the ADCC of the protein through improved FcγRIIIa binding without altering antigen binding or CDC activity.Such proteins have been reported to successfully express relatively highly defucosylated immunoglobulins with biantennary and complex type Fc oligosaccharides using different methods, such as controlling the culture osmolarity (Konno et al., Cytotechnology 64:249-65, 2012), applying the variant CHO line Lec13 as a host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), applying the variant CHO line EB66 as a host cell line (Olivier et al., MAbs;2(4):405-415, 2010; PMID:20562582), applying the rat hybridoma cell line YB2 / 0 as a host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introduction of small interfering RNA specific for the 1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expression of β-1,4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II or kifunensine, a potent alpha-mannosidase I inhibitor (Ferrara et al., J Biol Chem 281:5032-5036, 2006; Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Xhou et al., Biotechnol Bioeng 99:652-65, 2008).

[0398] In some embodiments, an antigen binding domain that binds CD79b conjugated to an Ig constant region or a fragment of an Ig constant region of the present disclosure has a biantennary glycan structure with a fucose content of about 1% to about 15%, e.g., about 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In some embodiments, an antigen binding domain that binds CD79b conjugated to an Ig constant region or a fragment of an Ig constant region has a glycan structure with a fucose content of about 50%, 40%, 45%, 40%, 35%, 30%, 25%, or 20%.

[0399] "Fucose content" refers to the amount of fucose monosaccharide in the glycan at Asn297. The relative amount of fucose is the percentage of all glycan structures containing fucose. These glycan structures can be determined in a number of ways, including, for example, 1) using MALDI-TOF of N-glycosidase F treated samples (e.g., complex, hybrid, and oligo- and high mannose structures) as described in WO 2008 / 077546 2, 2) enzymatic release of the Asn297 glycan followed by derivatization and detection / quantification by HPLC with fluorescence detection (UPLC) and / or HPLC-MS (UPLC-MS), 3) using Endo Glycosidase F, which cleaves between the first and second GlcNAc monosaccharides, leaving the fucose attached to the first GlcNAc. mAb oligosaccharides can be characterized and quantified by: intact protein analysis of native or reduced mAbs with or without treatment of the Asn297 glycan with S or other enzymes; 4) enzymatic digestion (e.g., trypsin or endopeptidase Lys-C) into constituent peptides of the mAb followed by separation, detection and quantification by HPLC-MS (UPLC-MS); and 5) specific enzymatic deglycosylation with PNGase F at Asn 297 to separate the mAb oligosaccharides from the mAb protein. The oligosaccharides thus released can be labeled with fluorophores and separated and identified by a variety of complementary techniques that allow for the fine characterization of glycan structures by matrix-assisted laser desorption ionization (MALDI) mass spectrometry by comparison of observed masses with theoretical masses, the determination of the degree of sialylation by ion-exchange HPLC (GlycoSep C), the separation and quantification of oligosaccharide types according to hydrophilicity criteria by normal-phase HPLC (GlycoSep N), and the separation and quantification of oligosaccharides by high performance capillary electrophoresis-laser induced fluorescence (HPCE-LIF).

[0400] "Low fucose" or "low fucose content" as used herein refers to an antigen binding domain that binds to CD79b conjugated to an Ig constant region or a fragment of an Ig constant region having a fucose content of about 1% to 15%.

[0401] "Normal fucose" or "normal fucose content" as used herein refers to an antigen binding domain that binds to CD79b conjugated to an Ig constant region or a fragment of an Ig constant region having a fucose content of greater than about 50%, typically greater than 80% or greater than 85%.

[0402] Anti-idiotype antibodies An anti-idiotypic antibody is an antibody that specifically binds to the antigen-binding domain that binds to CD79b of the present disclosure.

[0403] The present disclosure also provides an anti-idiotypic antibody that specifically binds to an antigen-binding domain that binds CD79b of the present disclosure.

[0404] The disclosure also provides an antigen binding domain that binds CD79b comprising a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138. In one embodiment, an anti-idiotypic antibody that specifically binds to an antigen binding domain that binds CD79b is VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or They comprise the VH and VL of SEQ ID NO: 137 and SEQ ID NO: 138, respectively.

[0405] Anti-idiotypic (Id) antibodies are antibodies that recognize an antigenic determinant (e.g., paratope or CDR) of an antibody. Id antibodies may or may not block the antigen. Antigen-blocking Ids can be used to detect free antigen-binding domains in a sample (e.g., antigen-binding domains that bind to CD79b of the present disclosure). Non-blocking Ids can be used to detect total antibodies in a sample (free, partially bound to antigen, or fully bound to antigen). Id antibodies can be prepared by immunizing an animal with the antibody against which the anti-Id is being prepared.

[0406] Anti-Id antibodies can also be used as immunogens to induce an immune response in yet another animal, generating so-called anti-anti-Id antibodies. An anti-anti-Id can be epitopically identical to the original antigen-binding domain from which the anti-Id was derived. Thus, by using antibodies against idiotypic determinants of the antigen-binding domain, it is possible to identify other clones expressing antigen-binding domains of identical specificity. Anti-Id antibodies can be varied (thereby producing anti-Id antibody variants) and / or derived by any suitable technique, such as those described elsewhere herein.

[0407] Immunoconjugates An antigen binding domain that binds CD79b, a protein comprising an antigen binding domain that binds CD79b, or a multispecific protein that comprises an antigen binding domain that binds CD79b (collectively referred to herein as CD79b binding proteins) of the present disclosure may be conjugated to a heterologous molecule.

[0408] In some embodiments, the heterologous molecule is a detectable label or a cytotoxic agent.

[0409] The present invention also provides an antigen-binding domain that binds to CD79b conjugated to a detectable label.

[0410] The present invention also provides a protein comprising an antigen-binding domain that binds CD79b conjugated to a detectable label.

[0411] The present invention also provides a multispecific protein comprising an antigen-binding domain that binds CD79b conjugated to a detectable label.

[0412] The present invention also provides an antigen-binding domain that binds to CD79b conjugated to a cytotoxic agent.

[0413] The invention also provides a protein comprising an antigen-binding domain that binds CD79b conjugated to a cytotoxic agent.

[0414] The invention also provides a multispecific protein comprising an antigen-binding domain that binds CD79b conjugated to a cytotoxic agent.

[0415] The CD79b binding proteins of the disclosure can be used to target therapeutic agents to CD79b-expressing cells.

[0416] In some embodiments, the detectable label is also a cytotoxic agent.

[0417] The CD79b binding proteins of the disclosure conjugated to a detectable label can be used to assess the expression of CD79b in various samples.

[0418] Detectable labels include compositions that, when conjugated to a CD79b binding protein of the disclosure, render the latter detectable via spectroscopic, photochemical, biochemical, immunochemical, or chemical means.

[0419] Exemplary detectable labels include radioisotopes, magnetic beads, metal beads, colloidal particles, fluorescent dyes, electron-dense reagents, enzymes (e.g., commonly used in ELISAs), biotin, digoxigenin, haptens, luminescent molecules, chemiluminescent molecules, fluorescent dyes, fluorophores, fluorescence quenchers, colored molecules, radioisotopes, scintillates, avidin, streptavidin, protein A, protein G, antibodies or fragments thereof, polyhistidine, Ni 2+ , Flag tags, myc tags, heavy metals, enzymes, alkaline phosphatase, peroxidase, luciferase, electron donors / acceptors, acridinium esters, and colorimetric substrates.

[0420] A detectable label may spontaneously emit a signal, such as when the detectable label is a radioisotope. In other cases, a detectable label emits a signal as a result of being stimulated by an external field.

[0421] Exemplary radioisotopes can be gamma-, Auger-, beta-, alpha-, or positron-emitting radioisotopes. Exemplary radioisotopes include: 3 H, 11 C. 13 C. 15 N, 18 F, 19 F, 55 Co, 57 Co, 60 Co,61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 72 As, 75 Br, 86 Y, 89 Zr, 90 Sr, 94m Tc, 99m Tc, 115 In, 123 1, 124 1, 125 I, 131 1, 211 At, 212 Bi, 213 Bi, 223 Ra, 226 Ra, 225 Ac, and 227 Ac are included.

[0422] Exemplary metal atoms include metals having atomic numbers greater than 20, such as calcium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, gallium, germanium, arsenic, selenium, bromine, krypton, rubidium, strontium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, indium, tin, antimony, tellurium, iodine, xenon, cesium, barium, lanthanum, hafnium, tantalum, tungsten, and rhenium atoms. , osmium atom, iridium atom, platinum atom, gold atom, mercury atom, thallium atom, lead atom, bismuth atom, francium atom, radium atom, actinium atom, cerium atom, praseodymium atom, neodymium atom, promethium atom, samarium atom, europium atom, gadolinium atom, terbium atom, dysprosium atom, holmium atom, erbium atom, thulium atom, ytterbium atom, lutetium atom, thorium atom, protactinium atom, uranium atom, neptunium atom, plutonium atom, americium atom, curium atom, berkelium atom, californium atom, einsteinium atom, fermium atom, mendelevium atom, nobelium atom, or lawrencium atom.

[0423] In some embodiments, the metal atom can be an alkaline earth metal having an atomic number greater than 20.

[0424] In some embodiments, the metal atom can be a lanthanide.

[0425] In some embodiments, the metal atom can be an actinide.

[0426] In some embodiments, the metal atom can be a transition metal.

[0427] In some embodiments, the metal atom can be a base metal.

[0428] In some embodiments, the metal atoms can be gold atoms, bismuth atoms, tantalum atoms, and gadolinium atoms.

[0429] In some embodiments, the metal atom can be a metal having an atomic number between 53 (ie, iodine) and 83 (ie, bismuth).

[0430] In some embodiments, the metal atom can be an atom suitable for magnetic resonance imaging.

[0431] The metal atom is Ba. 2+ , Bi 3+ , Cs + , Ca 2+ , Cr 2+ , Cr 3+ , Cr 6+ , Co 2+ , Co 3+ , Cu + , Cu 2+ , Cu 3+ , Ga 3+ , Gd 3+ , Au + , Au 3+ , Fe 2+ , Fe 3+ , F 3+ , Pb 2+ , Mn 2+ , Mn 3+ , Mn 4+ , Mn 7+ , Hg 2+ , Ni 2+ , Ni 3+ , Ag + , Sr 2+ , Sn 2+ , Sn 4+ , and Zn 2+ The metal ion may be in the form of a +1, +2, or +3 oxidation state, such as: The metal atom may include a metal oxide, such as iron oxide, manganese oxide, or gadolinium oxide.

[0432] Suitable dyes include any commercially available dye, such as, for example, 5(6)-carboxyfluorescein, IRDye 680RD maleimide, or IRDye 800CW, a ruthenium polypyridyl dye.

[0433] Suitable fluorophores are fluorescein isothiocyanate (FITC), fluorescein thiosemicarbazide, rhodamine, Texas Red, CyDye (e.g., Cy3, Cy5, Cy5.5), Alexa Fluors (e.g., Alexa488, Alexa555, Alexa594, Alexa647), near infrared (NIR) (700-900 nm) fluorescent dyes, and carbocyanine and aminostyryl dyes.

[0434] An antigen binding domain that binds to CD79b conjugated to a detectable label can be used as an imaging agent.

[0435] A protein that contains an antigen binding domain that binds to CD79b conjugated to a detectable label can be used as an imaging agent.

[0436] A multispecific protein comprising an antigen binding domain that binds to CD79b conjugated to a detectable label can be used as an imaging agent.

[0437] In some embodiments, the cytotoxic agent is a chemotherapeutic agent, a drug, a growth inhibitory agent, a toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or a fragment thereof), or a radioactive isotope (i.e., a radioconjugate).

[0438] In some embodiments, the cytotoxic agent is daunomycin, doxorubicin, methotrexate, vindesine, a bacterial toxin such as diphtheria toxin, ricin, geldanamycin, a maytansinoid, or a calicheamicin. A cytotoxic agent may elicit its cytotoxic or cytostatic effects by mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition.

[0439] In some embodiments, the cytotoxic agent is an enzymatically active toxin such as diphtheria A chain, unbound active fragments of diphtheria toxin, exotoxin A chain (Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogenin, restrictocin, phenomycin, enomycin, and trichothecenes.

[0440] In some embodiments, the cytotoxic agent is 212 Bi, 131 I, 131 In, 90 Y, and 186 Radioactive nuclides such as Re.

[0441] In some embodiments, the cytotoxic agent is a dolastatin or peptide analogs and derivatives of dolostatin, auristatin or monomethylauristatin phenylalanine. Exemplary molecules are disclosed in U.S. Patent Nos. 5,635,483 and 5,780,588. Dolastatins and auristatins interfere with microtubule dynamics, GTP hydrolysis, and nuclear and cell division (Woyke et al (2001) Antimicrob Agents and Chemother. 45(12):3580-3584) and have been shown to have anticancer and antifungal activity. Dolastatin and auristatin drug moieties can be attached to the antibodies of the invention via the N (amino) or C (carboxyl) termini of the peptide drug moiety (WO 02 / 088172) or via any cysteine ​​engineered into the antibody.

[0442] The CD79b binding proteins of the disclosure can be conjugated to a detectable label using known methods.

[0443] In some embodiments, the detectable label is complexed to a chelator.

[0444] In some embodiments, the detectable label is conjugated to the CD79b binding protein of the disclosure via a linker.

[0445] The detectable label or cytotoxic moiety can be linked directly or indirectly to the CD79b binding proteins of the disclosure using known methods. Suitable linkers are known in the art and include, for example, prosthetic groups, non-phenolic linkers (derivatives of N-succimidyl-benzoate, dodecaborate), chelating moieties of both macrocyclic and acyclic chelators, such as derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7,10,tetraacetic acid (DOTA), diethylenetriaminepentaacetic acid (DTA), and the like. avid, DTPA), derivatives of S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and derivatives of 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), N-succinimidyl-3-(2-pyridyldithiol)propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (e.g., dimethyl adipimidate HCl), active esters ( For example, disuccinimidyl suberate), aldehydes (e.g., glutaraldehyde), bisazide compounds (e.g., bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (e.g., bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (e.g., toluene 2,6-diisocyanate), and bis-active fluorine compounds (e.g., 1,5-difluoro-2,4-dinitrobenzene), as well as other chelating moieties. Suitable peptide linkers are well known.

[0446] In some embodiments, the CD79b binding proteins of the disclosure are cleared from the blood via renal clearance.

[0447] kit The present invention also provides a kit comprising an antigen-binding domain that binds to CD79b.

[0448] The present invention also provides a kit comprising a protein comprising an antigen-binding domain that binds to CD79b.

[0449] The present invention also provides kits comprising multispecific proteins comprising an antigen-binding domain that binds to CD79b.

[0450] The kits can be used for therapeutic uses and as diagnostic kits.

[0451] The kit can be used to detect the presence of CD79b in a sample.

[0452] In some embodiments, the kit comprises a CD79b binding protein of the present disclosure and a reagent for detecting the CD79b binding protein. The kit may include one or more other components, including instructions for use; other reagents, such as a label, a therapeutic agent, or an agent useful for chelation or otherwise coupling, an antibody to a label or therapeutic agent, or a radioprotective composition; a device or other material for preparing the antibody for administration; a pharma- ceutically acceptable carrier, and a device or other material for administration to a subject.

[0453] In some embodiments, the kit comprises an antigen binding domain that binds CD79b in a container, and instructions for use of the kit.

[0454] In some embodiments, the kit comprises a protein comprising an antigen binding domain that binds CD79b in a container, and instructions for use of the kit.

[0455] In some embodiments, the kit comprises a multispecific protein comprising an antigen binding domain that binds CD79b in a container and instructions for use of the kit.

[0456] In some embodiments, the antigen binding domain that binds CD79b in the kit is labeled.

[0457] In some embodiments, the protein in the kit that comprises an antigen binding domain that binds CD79b is labeled.

[0458] In some embodiments, the multispecific protein comprising an antigen binding domain that binds CD79b in the kit is labeled.

[0459] In some embodiments, the extracellular antigen binding domain that binds CD79b comprises a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138. VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or Each of the VH and VL domains comprises an antigen-binding domain that binds to CD79b, the VH and VL domains comprising SEQ ID NO: 137 and SEQ ID NO: 138, respectively.

[0460] Polynucleotides, host cells, and vectors The present invention also provides isolated polynucleotides encoding any of the CD79b binding proteins of the present disclosure, including an antigen binding domain that binds CD79b, a protein comprising an antigen binding domain that binds CD79b, a multispecific protein comprising an antigen binding domain that binds CD79b, and a chimeric antigen receptor (CAR) comprising an antigen binding domain that binds CD79b of the present disclosure.

[0461] The present invention also provides isolated polynucleotides encoding any of the CD79b binding proteins or fragments thereof.

[0462] In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131. In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising HCDR2 of SEQ ID NO:72, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132. In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0463] In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121 or SEQ ID NO:131; an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122 or SEQ ID NO:132; and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123 or SEQ ID NO:133.

[0464] In one embodiment, the isolated polynucleotide comprises: HCDR1, HCDR2, and HCDR3 of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:101, SEQ ID NO:102, and SEQ ID NO:103, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:121, SEQ ID NO:122, and SEQ ID NO:123, respectively; or Each encodes a CD79b binding protein comprising the HCDR1, HCDR2, and HCDR3 of SEQ ID NO:131, SEQ ID NO:132, and SEQ ID NO:133, respectively.

[0465] In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising a light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134. In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising a LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135. In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0466] In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124 or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125 or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126 or SEQ ID NO:136.

[0467] In one embodiment, the isolated polynucleotide comprises: LCDR, LCDR2, and LCDR3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; the LCDR, LCDR2, and LCDR3 of SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each encodes a CD79b binding protein comprising the LCDR, LCDR2, and LCDR3 of SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0468] In one embodiment, the isolated polynucleotide comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131; an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132; and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133. In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising an LDCR1 of sequence number 4, SEQ ID NO: 14, SEQ ID NO: 24, SEQ ID NO: 34, SEQ ID NO: 44, SEQ ID NO: 54, SEQ ID NO: 64, SEQ ID NO: 74, SEQ ID NO: 84, SEQ ID NO: 94, SEQ ID NO: 104, SEQ ID NO: 114, SEQ ID NO: 124, or SEQ ID NO: 134, an LCDR2 of SEQ ID NO: 5, SEQ ID NO: 15, SEQ ID NO: 25, SEQ ID NO: 35, SEQ ID NO: 45, SEQ ID NO: 55, SEQ ID NO: 65, SEQ ID NO: 75, SEQ ID NO: 85, SEQ ID NO: 95, SEQ ID NO: 105, SEQ ID NO: 115, SEQ ID NO: 125, or SEQ ID NO: 135, and an LCDR3 of SEQ ID NO: 6, SEQ ID NO: 16, SEQ ID NO: 26, SEQ ID NO: 36, SEQ ID NO: 46, SEQ ID NO: 56, SEQ ID NO: 66, SEQ ID NO: 76, SEQ ID NO: 86, SEQ ID NO: 96, SEQ ID NO: 106, SEQ ID NO: 116, SEQ ID NO: 126, or SEQ ID NO: 136. HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each encodes a CD79b binding protein comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0469] In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137.

[0470] In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0471] In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0472] In one embodiment, the isolated polynucleotide is VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or 137 and 138, respectively.

[0473] In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising a heavy chain (HC) of SEQ ID NO:9, SEQ ID NO:19, SEQ ID NO:29, SEQ ID NO:39, SEQ ID NO:49, SEQ ID NO:59, SEQ ID NO:69, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:99, SEQ ID NO:109, SEQ ID NO:119, SEQ ID NO:129, or SEQ ID NO:139.

[0474] In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising a light chain (LC) of SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:30, SEQ ID NO:40, SEQ ID NO:50, SEQ ID NO:60, SEQ ID NO:70, SEQ ID NO:80, SEQ ID NO:90, SEQ ID NO:100, SEQ ID NO:110, SEQ ID NO:120, SEQ ID NO:130, or SEQ ID NO:140.

[0475] In one embodiment, the isolated polynucleotide encodes a CD79b binding protein comprising a HC of SEQ ID NO:9, SEQ ID NO:19, SEQ ID NO:29, SEQ ID NO:39, SEQ ID NO:49, SEQ ID NO:59, SEQ ID NO:69, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:99, SEQ ID NO:109, SEQ ID NO:119, SEQ ID NO:129, or SEQ ID NO:139, and a LC of SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:30, SEQ ID NO:40, SEQ ID NO:50, SEQ ID NO:60, SEQ ID NO:70, SEQ ID NO:80, SEQ ID NO:90, SEQ ID NO:100, SEQ ID NO:110, SEQ ID NO:120, SEQ ID NO:130, or SEQ ID NO:140.

[0476] In one embodiment, the isolated polynucleotide is HC and LC of SEQ ID NO:9 and SEQ ID NO:10, respectively; HC and LC of SEQ ID NO:19 and SEQ ID NO:20, respectively; HC and LC of SEQ ID NO:29 and SEQ ID NO:30, respectively; HC and LC of SEQ ID NO:39 and SEQ ID NO:40, respectively; HC and LC of SEQ ID NO:49 and SEQ ID NO:50, respectively; HC and LC of SEQ ID NO:59 and SEQ ID NO:60, respectively; HC and LC of SEQ ID NO:69 and SEQ ID NO:70, respectively; HC and LC of SEQ ID NO:79 and SEQ ID NO:80, respectively; HC and LC of SEQ ID NO:89 and SEQ ID NO:90, respectively; HC and LC of SEQ ID NO:99 and SEQ ID NO:100, respectively; HC and LC of SEQ ID NO:109 and SEQ ID NO:110, respectively; HC and LC of SEQ ID NO:119 and SEQ ID NO:120, respectively; HC and LC of SEQ ID NO: 129 and SEQ ID NO: 130, respectively; or 139 and 140, respectively.

[0477] Some embodiments of the disclosure also provide isolated or purified nucleic acids comprising a polynucleotide encoding a CD79b binding protein of the disclosure or a polynucleotide complementary to a polynucleotide that hybridizes under stringent conditions to a polynucleotide encoding a CD79b binding protein of the disclosure.

[0478] Polynucleotides that hybridize under stringent conditions may hybridize under high stringency conditions. "High stringency conditions" means that a polynucleotide specifically hybridizes to a target sequence (any nucleotide sequence of the nucleic acids described herein) in a detectable amount stronger than non-specific hybridization. High stringency conditions include conditions that distinguish polynucleotides with exact complementary sequences or polynucleotides with only a few interspersed mismatches from random sequences that end up having several small regions (e.g., 3-12 bases) that match the nucleotide sequence. Such small complementary regions are more easily melted than full-length complements of 14-17 or more bases, making them easily distinguishable by high stringency hybridization. Relatively high stringency conditions include low salt and / or high temperature conditions, such as those provided by about 0.02-0.1 M NaCl or equivalent at a temperature of about 50-70°C. Such high stringency conditions tolerate little, if any, mismatch between the nucleotide sequence and the template or target strand and are particularly suitable for detecting expression of any of the CARs described herein. It is generally understood that conditions can be made more stringent by the addition of increasing amounts of formamide.

[0479] The polynucleotide sequences of the present disclosure may be operably linked to one or more control elements (e.g., promoters or enhancers) that direct the expression of the nucleotide sequence in the intended host cell. The polynucleotide may be a cDNA. The promoter may be a strong, weak, tissue-specific, inducible, or developmental stage-specific promoter. Exemplary promoters that may be used are hypoxanthine phosphoribosyl transferase (HPRT), adenosine deaminase, pyruvate kinase, beta actin, human myosin, human hemoglobin, human muscle creatine, and the like. In addition, many viral promoters function constitutively in eukaryotic cells and are suitable for use in the described embodiments. Such viral promoters include the Cytomegalovirus (CMV) immediate early promoter, the SV40 early and late promoters, the Mouse Mammary Tumor Virus (MMTV) promoter, the Moloney Leukemia Virus, the Human Immunodeficiency Virus (HIV), the Epstein Barr Virus (EBV), the Rous Sarcoma Virus (RSV), and other retroviral long terminal repeats (LTRs), and the Herpes Simplex Virus thymidine kinase promoter. Inducible promoters such as metallothionein promoter, tetracycline-inducible promoter, doxycycline-inducible promoter, protein kinase R2',5'-oligoadenylate synthetase, Mx gene, promoters containing one or more interferon-stimulated response elements (ISREs), such as ADAR1, may be used.

[0480] The present invention also provides vectors comprising the polynucleotides of the present invention. The present disclosure also provides expression vectors comprising the polynucleotides of the present invention. Such vectors may be plasmid vectors, viral vectors, vectors for baculovirus expression, transposon-based vectors, or any other vector suitable for introducing the synthetic polynucleotides of the present invention into a given organism or genetic background by any means. The polynucleotides encoding the CD79b binding proteins of the present disclosure may be operably linked to control sequences in the expression vector that ensure expression of the CD79b binding proteins. Such regulatory elements may include a transcription promoter, a sequence encoding a suitable mRNA ribosomal binding site, and sequences that control the termination of transcription and translation. The expression vector may also include one or more non-transcribed elements, such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, other 5' or 3' flanking non-transcribed sequences, 5' or 3' non-translated sequences (e.g., essential ribosomal binding sites), polyadenylation sites, splice donor and acceptor sites, or transcription termination sequences. An origin of replication that confers the ability to replicate in a host may also be incorporated.

[0481] Expression vectors can contain naturally occurring or non-naturally occurring internucleotide bonds, or both types of bonds. Non-naturally occurring or altered nucleotides or internucleotide linkages do not inhibit the transcription or replication of the vector.

[0482] Once the vector has been incorporated into a suitable host, the host is maintained under conditions suitable for high level expression of the CD79b binding protein of the present disclosure encoded by the incorporated polynucleotide. Transcriptional and translational control sequences in expression vectors used to transform vertebrate cells can be provided by viral sources. Exemplary vectors can be constructed as described by Okayama and Berg, 3 Mol. Cell. Biol. 280 (1983).

[0483] The vectors of the present disclosure may also contain one or more Internal Ribosome Entry Sites (IRES). The inclusion of an IRES sequence in a fusion vector may be beneficial for enhancing expression of some proteins. In some embodiments, the vector system includes one or more polyadenylation sites (e.g., SV40), which may be upstream or downstream of any of the aforementioned nucleic acid sequences. The components of the vector may be closely linked, or may be positioned or otherwise positioned to provide optimal spacing for expression of the gene product (i.e., by introducing "spacer" nucleotides between ORFs). Regulatory elements, such as IRES motifs, may also be positioned to provide optimal spacing for expression.

[0484] The vectors of the present disclosure may be circular or linear. They may be prepared to contain a replication system functional in prokaryotic or eukaryotic host cells. Replication systems may be derived, for example, from ColE1, SV40, 2μ plasmid, lambda, bovine papilloma virus, etc.

[0485] Recombinant expression vectors can be designed for either transient expression, stable expression, or both, and can be made for constitutive or inducible expression.

[0486] Additionally, the recombinant expression vector may be made to contain a suicide gene. As used herein, the term "suicide gene" refers to a gene that causes the death of a cell expressing the suicide gene. A suicide gene may be a gene that confers sensitivity to an agent (e.g., a drug) on ​​a cell expressing the gene, causing the cell to die when the cell is contacted or exposed to the agent. Suicide genes are known in the art and include, for example, Herpes Simplex Virus (HSV) thymidine kinase (TK) gene, cytosine deaminase, purine nucleoside phosphorylase, and nitroreductase.

[0487] The vector may also include a selection marker well known in the art. Selection markers include positive and negative selection markers. Marker genes include biocide resistance (e.g., resistance to antibiotics, heavy metals, etc.), complementation to provide prototrophy in auxotrophic hosts, etc. Exemplary marker genes include antibiotic resistance genes (e.g., neomycin resistance gene, hygromycin resistance gene, kanamycin resistance gene, tetracycline resistance gene, penicillin resistance gene, histidinol resistance gene, histidinol x resistance gene), glutamine synthetase gene, HSV-TK, HSV-TK derivatives for ganciclovir selection, or bacterial purine nucleoside phosphorylase gene for 6-methylpurine selection (Gadi et al., 7 Gene Ther. 1738-1743 (2000)) have been developed and widely adopted. The nucleic acid sequence or cloning site encoding the selection marker may be upstream or downstream of the nucleic acid sequence or cloning site encoding the polypeptide of interest.

[0488] Exemplary vectors that can be used are: bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene, La Jolla, Calif., USA); pTrc99A, pKK223-3, pKK233-3, pDR540, and pRIT5 (Pharmacia, Uppsala, Sweden). Eukaryotic: pWLneo, pSV2cat, pOG44, PXR1, pSG (Stratagene) pSVK3, pBPV, pMSG, and pSVL (Pharmacia), pEE6.4 (Lonza), and pEE12.4 (Lonza). Additional vectors include the pUC series (Fermentas Life Sciences, Glen Burnie, Md.), pBluescript series (Stratagene, LaJolla, Calif.), pET series (Novagen, Madison, Wis.), pGEX series (Pharmacia Biotech, Uppsala, Sweden), and pEX series (Clontech, Palo Alto, Calif.). Bacteriophage vectors such as λGT10, λGT11, λEMBL4, and λNM1149, λZapII (Stratagene) can be used. Exemplary plant expression vectors include pBI01, pBI01.2, pBI121, pBI101.3, and pBIN19 (Clontech). Exemplary animal expression vectors include pEUK-Cl, pMAM, and pMAMneo (Clontech). The expression vector can be a viral vector, such as a retroviral vector, for example a gamma retroviral vector.

[0489] In some embodiments, the vector comprises a polynucleotide encoding heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131.

[0490] In some embodiments, the vector comprises a polynucleotide encoding the HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132.

[0491] In some embodiments, the vector comprises a polynucleotide encoding the HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0492] In some embodiments, the vector comprises a polynucleotide encoding an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131; an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132; and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133.

[0493] In some embodiments, the vector is HCDR1, HCDR2, and HCDR3 of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO:43, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:93, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:101, SEQ ID NO:102, and SEQ ID NO:103, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:111, SEQ ID NO:112, and SEQ ID NO:113, respectively; HCDR1, HCDR2, and HCDR3 of SEQ ID NO:121, SEQ ID NO:122, and SEQ ID NO:123, respectively; or Each encodes a CD79b binding protein comprising the HCDR1, HCDR2, and HCDR3 of SEQ ID NO:131, SEQ ID NO:132, and SEQ ID NO:133, respectively.

[0494] In some embodiments, the vector comprises a polynucleotide encoding light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134.

[0495] In some embodiments, the vector comprises a polynucleotide encoding an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135.

[0496] In some embodiments, the vector comprises a polynucleotide encoding an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0497] In some embodiments, the vector comprises a polynucleotide encoding an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0498] In some embodiments, the vector comprises: LCDR, LCDR2, and LCDR3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; LCDR, LCDR2, and LCDR3 of SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; the LCDR, LCDR2, and LCDR3 of SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each encodes a CD79b binding protein comprising the LCDR, LCDR2, and LCDR3 of SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136, respectively.

[0499] In some embodiments, the vector comprises an HCDR1 of SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:21, SEQ ID NO:31, SEQ ID NO:41, SEQ ID NO:51, SEQ ID NO:61, SEQ ID NO:71, SEQ ID NO:81, SEQ ID NO:91, SEQ ID NO:101, SEQ ID NO:111, SEQ ID NO:121, or SEQ ID NO:131; an HCDR2 of SEQ ID NO:2, SEQ ID NO:12, SEQ ID NO:22, SEQ ID NO:32, SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:62, SEQ ID NO:72, SEQ ID NO:82, SEQ ID NO:92, SEQ ID NO:102, SEQ ID NO:112, SEQ ID NO:122, or SEQ ID NO:132; and an HCDR3 of SEQ ID NO:3, SEQ ID NO:13, SEQ ID NO:23, SEQ ID NO:33, SEQ ID NO:43, SEQ ID NO:53, SEQ ID NO:63, SEQ ID NO:73, SEQ ID NO:83, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:113, SEQ ID NO:123, or SEQ ID NO:133. The present invention includes a polynucleotide encoding an LDCR1 of SEQ ID NO:4, SEQ ID NO:14, SEQ ID NO:24, SEQ ID NO:34, SEQ ID NO:44, SEQ ID NO:54, SEQ ID NO:64, SEQ ID NO:74, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:114, SEQ ID NO:124, or SEQ ID NO:134; an LCDR2 of SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:35, SEQ ID NO:45, SEQ ID NO:55, SEQ ID NO:65, SEQ ID NO:75, SEQ ID NO:85, SEQ ID NO:95, SEQ ID NO:105, SEQ ID NO:115, SEQ ID NO:125, or SEQ ID NO:135; and an LCDR3 of SEQ ID NO:6, SEQ ID NO:16, SEQ ID NO:26, SEQ ID NO:36, SEQ ID NO:46, SEQ ID NO:56, SEQ ID NO:66, SEQ ID NO:76, SEQ ID NO:86, SEQ ID NO:96, SEQ ID NO:106, SEQ ID NO:116, SEQ ID NO:126, or SEQ ID NO:136.

[0500] In some embodiments, the vector comprises: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, and SEQ ID NO:96, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, and SEQ ID NO:106, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, and SEQ ID NO:116, respectively; HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, and SEQ ID NO:126, respectively; or Each of these includes a polynucleotide encoding HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, and SEQ ID NO:136.

[0501] In some embodiments, the vector comprises a polynucleotide encoding a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137.

[0502] In some embodiments, the vector comprises a polynucleotide encoding a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0503] In some embodiments, the vector comprises a polynucleotide encoding a VH of SEQ ID NO:7, SEQ ID NO:17, SEQ ID NO:27, SEQ ID NO:37, SEQ ID NO:47, SEQ ID NO:57, SEQ ID NO:67, SEQ ID NO:77, SEQ ID NO:87, SEQ ID NO:97, SEQ ID NO:107, SEQ ID NO:117, SEQ ID NO:127, or SEQ ID NO:137, and a VL of SEQ ID NO:8, SEQ ID NO:18, SEQ ID NO:28, SEQ ID NO:38, SEQ ID NO:48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:98, SEQ ID NO:108, SEQ ID NO:118, SEQ ID NO:128, or SEQ ID NO:138.

[0504] In some embodiments, the vector comprises: VH and VL of SEQ ID NO:7 and SEQ ID NO:8, respectively; VH and VL of SEQ ID NO: 17 and SEQ ID NO: 18, respectively; VH and VL of SEQ ID NO:27 and SEQ ID NO:28, respectively; VH and VL of SEQ ID NO:37 and SEQ ID NO:38, respectively; VH and VL of SEQ ID NO: 47 and SEQ ID NO: 48, respectively; VH and VL of SEQ ID NO:57 and SEQ ID NO:58, respectively; VH and VL of SEQ ID NO:67 and SEQ ID NO:68, respectively; VH and VL of SEQ ID NO: 77 and SEQ ID NO: 78, respectively; VH and VL of SEQ ID NO: 87 and SEQ ID NO: 88, respectively; VH and VL of SEQ ID NO:97 and SEQ ID NO:98, respectively; VH and VL of SEQ ID NO: 107 and SEQ ID NO: 108, respectively; VH and VL of SEQ ID NO: 117 and SEQ ID NO: 118, respectively; VH and VL of SEQ ID NO: 127 and SEQ ID NO: 128, respectively; or They include polynucleotides encoding the VH and VL of SEQ ID NO:137 and SEQ ID NO:138, respectively.

[0505] In one embodiment, the vector comprises a polynucleotide encoding the heavy chain (HC) of SEQ ID NO:9, SEQ ID NO:19, SEQ ID NO:29, SEQ ID NO:39, SEQ ID NO:49, SEQ ID NO:59, SEQ ID NO:69, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:99, SEQ ID NO:109, SEQ ID NO:119, SEQ ID NO:129, or SEQ ID NO:139.

[0506] In one embodiment, the vector comprises a polynucleotide encoding the light chain (LC) of SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:30, SEQ ID NO:40, SEQ ID NO:50, SEQ ID NO:60, SEQ ID NO:70, SEQ ID NO:80, SEQ ID NO:90, SEQ ID NO:100, SEQ ID NO:110, SEQ ID NO:120, SEQ ID NO:130, or SEQ ID NO:140.

[0507] In one embodiment, the vector comprises a polynucleotide encoding an HC of SEQ ID NO:9, SEQ ID NO:19, SEQ ID NO:29, SEQ ID NO:39, SEQ ID NO:49, SEQ ID NO:59, SEQ ID NO:69, SEQ ID NO:79, SEQ ID NO:89, SEQ ID NO:99, SEQ ID NO:109, SEQ ID NO:119, SEQ ID NO:129, or SEQ ID NO:139, and an LC of SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:30, SEQ ID NO:40, SEQ ID NO:50, SEQ ID NO:60, SEQ ID NO:70, SEQ ID NO:80, SEQ ID NO:90, SEQ ID NO:100, SEQ ID NO:110, SEQ ID NO:120, SEQ ID NO:130, or SEQ ID NO:140.

[0508] In one embodiment, the vector comprises: HC and LC of SEQ ID NO:9 and SEQ ID NO:10, respectively; HC and LC of SEQ ID NO:19 and SEQ ID NO:20, respectively; HC and LC of SEQ ID NO:29 and SEQ ID NO:30, respectively; HC and LC of SEQ ID NO:39 and SEQ ID NO:40, respectively; HC and LC of SEQ ID NO:49 and SEQ ID NO:50, respectively; HC and LC of SEQ ID NO:59 and SEQ ID NO:60, respectively; HC and LC of SEQ ID NO:69 and SEQ ID NO:70, respectively; HC and LC of SEQ ID NO:79 and SEQ ID NO:80, respectively; HC and LC of SEQ ID NO:89 and SEQ ID NO:90, respectively; HC and LC of SEQ ID NO:99 and SEQ ID NO:100, respectively; HC and LC of SEQ ID NO:109 and SEQ ID NO:110, respectively; HC and LC of SEQ ID NO:119 and SEQ ID NO:120, respectively; HC and LC of SEQ ID NO: 129 and SEQ ID NO: 130, respectively; or The polynucleotides encoding the HC and LC are SEQ ID NO:139 and SEQ ID NO:140, respectively.

[0509] An embodiment of the present invention further provides a host cell comprising any of the recombinant expression vectors described herein. "Host cell" refers to a cell into which a vector has been introduced. It is understood that the term host cell is intended to refer not only to the particular subject cell, but also to the progeny of such a cell, as well as to stable cell lines generated from the particular subject cell. Such progeny may not be identical to the parent cell, as certain modifications may occur in subsequent generations, either due to mutation or environmental influences, but are still included within the scope of the term "host cell" as used herein. Such host cells may be eukaryotic, prokaryotic, plant, or archaeal cells. Examples of prokaryotic host cells are Escherichia coli, bacilli such as Bacillus subtilis, and other Enterobacteriaceae such as Salmonella, Serratia, and various Pseudomonas species. Other microorganisms, such as yeast, are also useful for expression. Examples of suitable yeast host cells are Saccharomyces (e.g., S. cerevisiae) and Pichia. Exemplary eukaryotic cells may be of mammalian, insect, avian, or other animal origin. Mammalian eukaryotic cells include immortalized cell lines such as hybridoma or myeloma cell lines, such as SP2 / 0 (American Type Culture Collection (ATCC), Manassas, VA, CRL-1581), NS0 (European Collection of Cell Cultures (ECACC), Salisbury, Wiltshire, UK, ECACC No. 85110503), FO (ATCC CRL-1646), and Ag653 (ATCC CRL-1580) murine cell lines. An exemplary human myeloma cell line is U266 (ATTC CRL-TIB-196).Other useful cell lines include those derived from Chinese Hamster Ovary (CHO) cells, such as CHO-K1SV (Lonza Biologics, Walkersville, MD), CHO-K1 (ATCC CRL-61), or DG44.

[0510] The host cells can be cultured or primary cells, i.e., directly isolated from an organism, e.g., a human. The host cells can be adherent or floating cells, i.e., cells that grow in suspension. Suitable host cells are known in the art, and include, for example, DH5α E.coli cells, Chinese hamster ovary cells, monkey VERO cells, COS cells, HEK293 cells, etc. For the purposes of amplifying or replicating a recombinant expression vector, the host cell can be a prokaryotic cell, e.g., DH5α cell. For the purposes of producing a recombinant CAR, polypeptide, or protein, the host cell can be a mammalian cell. The host cell can be a human cell. The host cell can be of any cell type, derived from any tissue type, and at any developmental stage, but the host cell can be a peripheral blood lymphocyte (PBL). The host cell can be a T cell.

[0511] Also provided are cell populations comprising at least one host cell described herein. The cell population can be a heterogeneous population comprising host cells comprising any of the described recombinant expression vectors in addition to at least one other cell, e.g., a host cell not comprising any of the recombinant expression vectors (e.g., a T cell), or a cell other than a T cell (e.g., a B cell, a macrophage, an erythrocyte, a neutrophil, a hepatocyte, an endothelial cell, an epithelial cell, a muscle cell, a brain cell, etc.). Alternatively, the cell population can be a substantially homogeneous population, in which the population comprises primarily (e.g., consists essentially of) host cells comprising the recombinant expression vector. The population can also be a clonal population of cells, in which all cells of the population are clones of a single host cell comprising the recombinant expression vector, and therefore all cells of the population comprise the recombinant expression vector. In one embodiment, the cell population is a clonal population comprising host cells comprising the recombinant expression vector described herein.

[0512] The present disclosure also provides a method of producing a CD79b binding protein of the present disclosure, comprising culturing a host cell of the present disclosure under conditions in which the CD79b binding protein is expressed and recovering the CD79b binding protein produced by the host cell. Methods of making proteins and purifying them are known. Once synthesized (chemically or recombinantly), CD79b binding proteins can be purified according to standard procedures including ammonium sulfate precipitation, affinity columns, column chromatography, high performance liquid chromatography (HPLC) purification, gel electrophoresis, and the like (see generally, Scopes, Protein Purification, Springer-Verlag, NY, (1982)). The protein of interest can be substantially pure, e.g., at least about 80%-85% pure, at least about 85%-90% pure, at least about 90%-95% pure, or at least about 98%-99% pure, or more, and can be free of contaminants such as cellular debris, macromolecules other than the protein of interest, and the like.

[0513] A polynucleotide encoding a CD79b binding protein of the present disclosure can be incorporated into a vector using standard molecular biology techniques. Transformation of host cells, culture, antibody expression, and purification are carried out using well-known methods.

[0514] Modified nucleotides can be used to generate the polynucleotides of the present disclosure. Exemplary modified nucleotides include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, N 6 -Substituted adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueuosine, 5"-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N 6 -Isopentenyladenine, uracil-5-oxyacetate (v), wybutoxosine, pseudouracil, queuosine, beta-D-galactosylqueuosine, inosine, N 6 -isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, 3-(3-amino-3-N-2-carboxypropyl)uracil, and 2,6-diaminopurine.

[0515] Pharmaceutical Composition / Administration The present invention also provides a pharmaceutical composition comprising a CD79b binding protein of the disclosure and a pharma- ceutically acceptable carrier.

[0516] The present disclosure also provides a pharmaceutical composition comprising an antigen-binding domain that binds CD79b of the present disclosure and a pharma- ceutically acceptable carrier.

[0517] The present disclosure also provides a pharmaceutical composition comprising a protein comprising an antigen-binding domain that binds to CD79b of the present disclosure and a pharma- ceutically acceptable carrier.

[0518] The present disclosure also provides a pharmaceutical composition comprising a multispecific protein comprising an antigen-binding domain that binds to CD79b of the present disclosure and a pharma- ceutical acceptable carrier.

[0519] The present disclosure also provides a pharmaceutical composition comprising an antigen-binding domain that binds CD79b of the present disclosure and a pharma- ceutically acceptable carrier.

[0520] For therapeutic applications, the CD79b binding proteins of the present disclosure can be prepared as pharmaceutical compositions containing an effective amount of the antibody as an active ingredient in a pharma- ceutically acceptable carrier. "Carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the present invention is administered. Such vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, 0.4% saline and 0.3% glycine may be used. These solutions are sterile and generally free of particulate matter. They can be sterilized by conventional, well-known sterilization techniques (e.g., filtration). The compositions can contain pharma- ceutical acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, stabilizers, thickening agents, lubricants, and coloring agents. The concentration of the CD79 binding proteins of the invention in such pharmaceutical formulations can vary from less than about 0.5% by weight, usually to at least about 1% by weight, up to 15 or 20% by weight, and can be selected primarily based on the required dose, fluid volumes, viscosities, etc., according to the method of administration selected. Suitable vehicles and formulations (including other human proteins, such as human serum albumin) are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Edition, Troy, DBed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, see in particular pp. 958-989.

[0521] The mode of administration of the CD79b binding proteins of the disclosure may be by any suitable route, such as parenteral administration, e.g., intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous, transmucosal (oral, intranasal, intravaginal, rectal), or other means understood by one of skill in the art, as is well known in the art.

[0522] The CD79b binding proteins of the present disclosure can also be administered prophylactically to reduce the risk of developing a disease, such as cancer.

[0523] Thus, a pharmaceutical composition of the invention for intramuscular injection can be prepared to contain 1 ml of sterile buffered water and from about 1 ng to about 100 mg / kg, for example from about 50 ng to about 30 mg / kg, or more preferably from about 5 mg to about 25 mg / kg, of a CD79b binding protein of the invention.

[0524] In an embodiment of the disclosure, the CD79b binding protein expressing cells may be provided in a composition, e.g., a suitable pharmaceutical composition comprising a CD79b binding protein expressing cell and a pharma- ceutically acceptable carrier. In one aspect, the disclosure provides a pharmaceutical composition comprising an effective amount of lymphocytes expressing one or more CD79b binding proteins as described and a pharma- ceutically acceptable excipient. The pharmaceutical composition of the disclosure may comprise a CD79b binding protein expressing cell, e.g., a plurality of CD79b binding protein expressing cells as described herein, in combination with one or more pharma- ceutically or physiologically acceptable carriers, excipients, or diluents. A pharma- ceutically acceptable carrier may be an ingredient in a pharmaceutical composition other than the active ingredient that is non-toxic to a subject.

[0525] Pharmaceutically acceptable carriers can include buffers, excipients, stabilizers, or preservatives. Examples of pharma-ceutically acceptable carriers include physiologically compatible solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption retarding agents, and the like, such as salts, buffer solutions, antioxidants, sugars, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants, or emulsifiers, or combinations thereof. The amount of pharma-ceutically acceptable carrier in a pharmaceutical composition can be empirically determined based on the activity of the carrier and the desired properties of the formulation, such as stability and / or minimal oxidation.

[0526] The pharmaceutical compositions may include buffers such as acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffer, HEPPSO, HEPES, neutral buffered saline, phosphate buffered saline; carbohydrates such as glucose, mannose, sucrose or dextran, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); antibacterial and antifungal agents; and preservatives.

[0527] The pharmaceutical compositions of the present disclosure can be formulated for various means of parenteral or oral administration. In one embodiment, the compositions can be formulated for injection or intravenous administration. The pharmaceutical compositions disclosed herein can be provided, for example, as sterile liquid preparations, such as isotonic aqueous solutions, emulsions, suspensions, dispersions, or viscous compositions, which can be buffered to a desired pH. Preparations suitable for oral administration can include liquid solutions, capsules, sachets, tablets, drops, and lozenges, liquid suspensions of powders in appropriate liquids and emulsions.

[0528] As used herein with respect to pharmaceutical compositions, the term "pharmaceutical acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals and / or humans.

[0529] How to detect CD79B The invention also provides a method of detecting CD79b in a sample, comprising obtaining the sample, contacting the sample with an antigen binding domain that binds CD79b of the present disclosure, and detecting bound CD79b in the sample.

[0530] In some embodiments, samples may be derived from urine, blood, serum, plasma, saliva, peritoneal fluid, circulating cells, synovial fluid, circulating cells, cells not associated with tissue (i.e., free cells), tissue (e.g., biopsies, including surgically removed tissue, fine needle aspirates), tissue preparations, and the like.

[0531] Antigen binding domains of the present disclosure that bind to CD79b can be detected using known methods. Exemplary methods include directly labeling the antibody using a fluorescent or chemiluminescent label, or a radiolabel, or coupling an easily detectable moiety, such as biotin, an enzyme, or an epitope tag, to an antibody of the invention. Exemplary labels and moieties include ruthenium, 111 In-DOTA, 111 In-diethylenetriaminepentaacetic acid (DTPA), horseradish peroxidase, alkaline phosphatase and beta-galactosidase, poly-histidine (HIS tag), acridine dyes, cyanine dyes, fluorone dyes, oxazine dyes, phenanthridine dyes, rhodamine dyes, and Alexafluor® dyes.

[0532] The antigen binding domains that bind CD79b of the present disclosure may be used in a variety of assays to detect CD79b in a sample. Exemplary assays are Western blot analysis, radioimmunoassay, surface plasmon resonance, immunoprecipitation, equilibrium dialysis, immunodiffusion, electrochemiluminescence (ECL) immunoassay, immunohistochemistry, fluorescence-activated cell sorting (FACS), or ELISA assays.

[0533] Treatment and Methods of Use An antigen binding domain that binds CD79b of the present disclosure can be administered to a subject in need thereof to combat, treat, prevent, or ameliorate an autoimmune disease or disorder, or one or more symptoms thereof.

[0534] The present disclosure also provides a method comprising administering to a subject having an autoimmune disease a therapeutically effective amount of an antigen binding domain that binds CD79b of the present disclosure.

[0535] The present disclosure also provides a method comprising administering to a subject having an autoimmune disease a therapeutically effective amount of a protein comprising an antigen-binding domain that binds CD79b of the present disclosure.

[0536] The present disclosure also provides a method comprising administering to a subject having an autoimmune disease a therapeutically effective amount of a multispecific protein comprising an antigen-binding domain that binds CD79b of the present disclosure.

[0537] The present disclosure also provides a method comprising administering to a subject having an autoimmune disease a therapeutically effective amount of an antigen binding domain that binds CD79b of the present disclosure.

[0538] The present disclosure also provides a method comprising administering to a subject having an autoimmune disease a therapeutically effective amount of an immunoconjugate comprising an antigen-...

Claims

[Claim 1] The invention described in this specification.