HUMANIZED AND AFFINITY MATURED ANTIBODIES TO FcRH5 AND METHODS OF USE

• US 20160368985A1
• Filed: 06/16/2016
• Published: 12/22/2016
• Est. Priority Date: 06/16/2015
• Status: Active Grant

• Current Assignee: F Hoffmann-La Roche AG (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: LI, Ji, SCHEER, Justin, DICARA, Danielle, ELLERMAN, Diego, SPIESS, Christoph, HOTZEL, Isidro, JUNTTILA, Teemu T., CARTER, Paul J.
• Granted Patent: US 10,323,094 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/283 against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/62 : comprising only variable region components
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: G01N 2333/70535 : Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
• CPC Class Codes: G01N 33/57492 : involving compounds localized on the membrane of tumor or cancer cells

Abstract

The present invention relates to anti-FcRH5 antibodies, including anti-FcRH5 antibodies comprising an FcRH5 binding domain and a CD3 binding domain (e.g., FcRH5 T cell-dependent bispecific (TDB) antibodies), and methods of using the same.

Claims

1. An anti-Fc Receptor-like 5 (FcRH5) antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six hypervariable regions (HVRs):

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

2;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

3;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

4;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

5; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

6.

114. The anti-FcRH5 antibody of claim 1, wherein the anti-FcRH5 antibody binds to an epitope in the Ig-like domain 9 of FcRH5.

115. The anti-FcRH5 antibody of claim 114, wherein the epitope comprises a portion of amino acids 743-850 of SEQ ID NO:

114.

116. The anti-FcRH5 antibody of claim 114, wherein the binding domain binds to human FcRH5 or cynomolgus monkey (cyno) FcRH5 or both.

117. The anti-FcRH5 antibody of claim 116, wherein the binding domain does not specifically bind to FcRH1, FcRH2, FcRH3, and/or FcRH4.

119. The anti-FcRH5 antibody of claim 116, wherein the anti-FcRH5 antibody binds human and/or cyno FcRH5 with a K_D of between about 10 pM and about 100 nM.

127. The anti-FcRH5 antibody of claim 1, wherein the anti-FcRH5 antibody comprises an aglycosylation site mutation.

140. The anti-FcRH5 antibody of claim 1, wherein the anti-FcRH5 antibody is a multispecific antibody.

141. The anti-FcRH5 antibody of claim 140, wherein the multispecific antibody is a bispecific antibody.

142. The anti-FcRH5 antibody of claim 141, wherein the bispecific antibody comprises a second binding domain that binds cluster of differentiation 3 (CD3).

143. The anti-FcRH5 antibody of claim 142, wherein the second binding domain binds to an epitope on CD3 comprising amino acid residue Glu6 of CD3.

150. The anti-FcRH5 antibody of claim 143, wherein the second binding domain is capable of binding to a human CD3 polypeptide or a cyno CD3 polypeptide.

157. The anti-FcRH5 antibody of claim 142, wherein the second binding domain comprises the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

115;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

116;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

117;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

118;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

119; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

120.

179. The anti-FcRH5 antibody of claim 142, wherein the second binding domain comprises the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

155;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

156;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

157;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

158;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

159; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

160.

187. The anti-FcRH5 antibody of claim 142, wherein the binding domain that binds FcRH5 comprises a VH domain (VH₁) comprising a charged region (CR₁) and a VL domain (VL₁) comprising a charged region (CR₂), wherein the CR₁ in the VH₁ forms a charge pair with the CR₂ in the VL₁.

193. The anti-FcRH5 antibody of claim 187, wherein the second binding domain that binds CD3 comprises a VH domain (VH₂) comprising a charged region (CR₃) and a VL domain (VL₂) comprising a charged region (CR₄), wherein the CR₄ in the VL₂ forms a charge pair with the CR₃ in the VH₂.

199. The anti-FcRH5 antibody of claim 187, wherein the VL₁ domain is linked to a light chain constant (CL) domain (CL₁) and the VH₁ is linked to a first heavy chain constant (CH1) domain (CH1₁), wherein the CL₁ comprises a charged region (CR₅) and the CH1₁ comprises a charged region (CR₆), and wherein the CR₅ in the CL₁ forms a charge pair with the CR₆ in the CH1₁.

205. The anti-FcRH5 antibody of claim 199, wherein the VL₂ domain is linked to a CL domain (CL₂) and the VH₂ is linked to a CH1 domain (CH1₂), wherein the CL₂ comprises a charged region (CR₇) and the CH1₂ comprise a charged region (CR₈), and wherein the CR₈ in the CH1₂ forms a charge pair with the CR₇ in the CL₂.

211. The anti-FcRH5 antibody of claim 199, wherein the VL₂ domain is linked to a CL domain (CL₂) and the VH₂ is linked to a CH1 domain (CH1₂), wherein (a) the CL₂ comprises one or more mutations at amino acid residues F116, L135, S174, S176, and/or T178 (EU numbering) and (b) the CH1₂ comprises one or more mutations at amino acid residues A141, F170, S181, S183, and/or V185 (EU numbering).

216. The anti-FcRH5 antibody of claim 142, wherein the binding domain that binds FcRH5 comprises a VH domain (VH₁) comprising a charged region (CR₁) and a VL domain (VL₁) comprising a charged region (CR₂), wherein the CR₂ in the VL₁ forms a charge pair with the CR₁ in the VH₁.

222. The anti-FcRH5 antibody of claim 216, wherein the second binding domain that binds CD3 comprises a VH domain (VH₂) comprising a charged region (CR₃) and a VL domain (VL₂) comprising a charged region (CR₄), wherein the CR₃ in the VH₂ forms a charge pair with the CR₄ in the VL₂.

228. The anti-FcRH5 antibody of claim 216, wherein the VL₁ domain is linked to a light chain constant (CL) domain (CL₁) and the VH₁ is linked to a first heavy chain constant (CH1) domain (CH1₁), wherein the CL₁ comprises a charged region (CR₅) and the CH1₁ comprises a charged region (CR₆), and wherein the CR₆ in the CH1₁ forms a charge pair with the CR₅ in the CL₁.

234. The anti-FcRH5 antibody of claim 228, wherein the VL₂ domain is linked to a CL domain (CL₂) and the VH₂ is linked to a CH1 domain (CH1₂), wherein the CL₂ comprises a charged region (CR₇) and the CH1₂ comprises a charged region (CR₈), and wherein the CR₇ in the CL₂ forms a charged pair with the CR₈ in the CH1₂.

240. The anti-FcRH5 antibody of claim 228, wherein the VL₂ domain is linked to a CL domain (CL₂) and the VH₂ is linked to a CH1 domain (CH1₂), wherein (a) the CL₂ comprises one or more mutations at amino acid residues F116, L135, S174, S176, and/or T178 (EU numbering) and (b) the CH1₂ comprises one or more mutations at amino acid residues A141, F170, S181, S183, and/or V185 (EU numbering).

245. The anti-FcRH5 antibody of claim 187, wherein the anti-FcRH5 antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH2 domain (CH2₁), a first CH3 domain (CH3₁), a second CH2 domain (CH2₂), and a second CH3 domain (CH3₂).

249. The anti-FcRH5 antibody of claim 245, wherein the CH2₁ and the CH2₂ each comprise (P₂) or a cavity (C₂), and wherein the P₂ or the C₂ in the CH2₁ is positionable in the C₂ or the P₂, respectively, in the CH2₂.

260. The anti-FcRH5 antibody of claim 1, wherein the anti-FcRH5 antibody has a clearance following intravenous injection of between about 10 ml/kg/day to about 35 ml/kg/day.

266. An isolated nucleic acid encoding the anti-FcRH5 antibody of claim 1, or a portion thereof comprising a binding domain thereof that binds to FcRH5.

267. A vector comprising the isolated nucleic acid of claim 266.

268. A host cell comprising the vector of claim 267.

273. A method of producing the anti-FcRH5 antibody of claim 1, the method comprising culturing the host cell of claim 268 in a culture medium.

274. The method of claim 273, wherein the method further comprises recovering the anti-FcRH5 antibody from the host cell or the culture medium.

275. The method of claim 273, further comprising culturing a second host cell comprising a second nucleic acid encoding an anti-CD3 antibody that comprises a binding domain that binds CD3.

276. The method of claim 275, wherein the host cells are co-cultured.

278. An immunoconjugate comprising the anti-FcRH5 antibody of claim 1 and a cytotoxic agent.

279. A composition comprising the anti-FcRH5 antibody of claim 1.

282. The composition of claim 279, wherein the composition is a pharmaceutical composition.

283. The composition of claim 279, wherein the composition further comprises a PD-1 axis binding antagonist or an additional therapeutic agent.

295. A method of treating or delaying the progression of an FcRH5-positive cancer in a subject in need thereof, the method comprising administering to the subject the anti-FcRH5 antibody of claim 1.

296. A method of enhancing immune function in a subject having an FcRH5-positive cancer, the method comprising administering to the subject an effective amount of the anti-FcRH5 antibody of claim 1.

297. The method of claim 295, wherein the FcRH5-positive cancer is a B cell cancer.

299. The method of claim 297, wherein the B cell cancer is MM.

310. The method of claim 295, further comprising administering to the subject a PD-1 axis binding antagonist and/or an additional therapeutic agent.

314. The method of claim 310, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

315. The method of claim 314, wherein the PD-L1 binding antagonist is selected from the group consisting of MPDL3280A (atezolizumab), YW243.55.S70, MDX-1105, MEDI4736 (durvalumab), and MSB0010718C (avelumab).

329. The method of claim 295, wherein the subject is a human.

330. A method for detecting FcRH5 in a biological sample from a subject, wherein the method comprises:

(a) contacting the biological sample with the anti-FcRH5 antibody of claim 1 under conditions permissive for binding of the anti-FcRH5 antibody to a naturally occurring FcRH5 in the biological sample, and

(b) detecting whether a complex is formed between the anti-FcRH5 antibody and a naturally occurring FcRH5 in the biological sample.

333. A kit comprising the antibody of claim 1 and a package insert comprising instructions for using the antibody for treating or delaying progression of an FcRH5-positive cancer in a subject.

334. A kit comprising the antibody of claim 1 and a package insert comprising instructions for using the antibody for enhancing immune function in a subject having an FcRH5-positive cancer.

2. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

8;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

16; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

23.

3. The anti-FcRH5 antibody of claim 2, wherein the binding domain comprises (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:

104;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

105;

or (c) a VH domain as in (a) and a VL domain as in (b).

4. The anti-FcRH5 antibody of claim 2, wherein the antibody further comprises the following heavy chain variable region framework regions (FRs):

(a) an FR-H1 comprising the amino acid sequence of SEQ ID NO;

52;

(b) an FR-H2 comprising the amino acid sequence of SEQ ID NO;

54;

(c) an FR-H3 comprising the amino acid sequence of SEQ ID NO;

46; and

(d) an FR-H4 comprising the amino acid sequence of SEQ ID NO;

47.

5. The anti-FcRH5 antibody of claim 4, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

104.

6. The anti-FcRH5 antibody of claim 2, wherein the antibody further comprises the following light chain variable region FRs:

(a) an FR-L1 comprising the amino acid sequence of SEQ ID NO;

48;

(b) an FR-L2 comprising the amino acid sequence of SEQ ID NO;

57;

(c) an FR-L3 comprising the amino acid sequence of SEQ ID NO;

50; and

(d) an FR-L4 comprising the amino acid sequence of SEQ ID NO;

51.

7. The anti-FcRH5 antibody of claim 6, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:

105.

8. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO:

104 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO;

105.

9. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

8;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

10;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

14;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

16; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

23.

10. The anti-FcRH5 antibody of claim 9, wherein the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:

106;

(b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

107;

or (c) a VH domain as in (a) and a VL domain as in (b).

11. The anti-FcRH5 antibody of claim 9, wherein the antibody further comprises the following heavy chain variable region FRs:

(a) an FR-H1 comprising the amino acid sequence of SEQ ID NO;

53;

(b) an FR-H2 comprising the amino acid sequence of SEQ ID NO;

54;

(c) an FR-H3 comprising the amino acid sequence of SEQ ID NO;

46; and

(d) an FR-H4 comprising the amino acid sequence of SEQ ID NO;

47.

12. The anti-FcRH5 antibody of claim 11, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

106.

13. The anti-FcRH5 antibody of claim 9, wherein the antibody further comprises the following light chain variable region FRs:

(a) an FR-L1 comprising the amino acid sequence of SEQ ID NO;

48;

(b) an FR-L2 comprising the amino acid sequence of SEQ ID NO;

57;

(c) an FR-L3 comprising the amino acid sequence of SEQ ID NO;

50; and

(d) an FR-L4 comprising the amino acid sequence of SEQ ID NO;

51.

14. The anti-FcRH5 antibody of claim 13, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:

107.

15. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO:

106 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO;

107.

16. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

7;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

11;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

15; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

20.

17-22. -22. (canceled)

23. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

7;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

16; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

21.

24-29. -29. (canceled)

30. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

7;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

17; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

22.

31-36. -36. (canceled)

37. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

7;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

13;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

16; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

21.

38-43. -43. (canceled)

44. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

7;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

16; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

23.

45-50. -50. (canceled)

51. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

7;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

11;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

18; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

22.

52-57. -57. (canceled)

58. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

7;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

11;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

19; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

24.

59-64. -64. (canceled)

65. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

7;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

18; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

25.

66-71. -71. (canceled)

72. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

7;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

18; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

25.

73-78. -78. (canceled)

79. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

7;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

18; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

25.

80-85. -85. (canceled)

86. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

8;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

11;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

15; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

20.

87-92. -92. (canceled)

93. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

32;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

33;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

34;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

35;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

36; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

37.

94-99. -99. (canceled)

100. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

38;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

39;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

40;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

41;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

42; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

43.

101-106. -106. (canceled)

107. An anti-FcRH5 antibody, wherein the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

26;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

27;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

28;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

29;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

30; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

31.

108-113. -113. (canceled)

118. (canceled)

120-126. -126. (canceled)

128-139. -139. (canceled)

144-149. -149. (canceled)

151-156. -156. (canceled)

158-178. -178. (canceled)

180-186. -186. (canceled)

188-192. -192. (canceled)

194-198. -198. (canceled)

200-204. -204. (canceled)

206-210. -210. (canceled)

212-215. -215. (canceled)

217-221. -221. (canceled)

223-227. -227. (canceled)

229-233. -233. (canceled)

235-239. -239. (canceled)

241-244. -244. (canceled)

246-248. -248. (canceled)

250. (canceled)

251. An anti-FcRH5 antibody that binds to FcRH5 and CD3, wherein the anti-FcRH5 antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

1;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

8;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

9;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

16; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

23; and

an anti-CD3 arm comprising a second binding domain comprising the following six HVRs;

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

115;

(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

116;

(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

121;

(d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

118;

(e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

119; and

(f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

123.

252-259. -259. (canceled)

261-265. -265. (canceled)

269-272. -272. (canceled)

277. (canceled)

280-281. -281. (canceled)

284-294. -294. (canceled)

298. (canceled)

300-309. -309. (canceled)

311-313. -313. (canceled)

316-328. -328. (canceled)

331-332. -332. (canceled)

335. (canceled)