Anti-CLL-1 antibodies and methods of use

Patent metadata

Field	Value
Publication number	US-10501545-B2
Application number	US-201615182327-A
Country	US
Kind code	B2
Filing date	Jun 14, 2016
Priority date	Jun 16, 2015
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

The present invention relates to anti-CLL-1 antibodies including anti-CLL-1 antibodies comprising a CLL-1 binding domain and a CD3 binding domain (e.g., anti-CLL-1/CD3 T cell dependent bispecific (TDB) antibody) and methods of using the same.

First claim

What is claimed is:

1. An isolated anti-CLL-1 antibody, wherein the antibody comprises:
(a) a CLL-1 binding domain, wherein the CLL-1 binding domain comprises six hypervariable regions (HVRs) as follows:
(i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 5, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 45 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 10; or
(ii) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 15, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 16 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; or
(iii) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 18, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 19, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20, an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; or
(iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 27, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 28 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 29; and
(b) a CD3 binding domain, wherein the CD3 binding domain comprises six HVRs as follows:
(i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 74, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 75, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 76, an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 71, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 72 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 73; or
(ii) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 74, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 80, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 76, an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 77, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 78 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 79; or
(iii) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 74, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 80, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 81, an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 77, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 78 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 79.

2. The anti-CLL-1 antibody of claim 1 , wherein the CLL-1 binding domain comprises the following six hypervariable regions (HVRs): (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:8; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:45; (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:5; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.

3. The anti-CLL-1 antibody of claim 2 , wherein the CLL-1 binding domain comprises HVR-H2 comprising the amino acid sequence of SEQ ID NO:9.

4. The anti-CLL-1 antibody of claim 2 , wherein the CLL-1 binding domain comprises HVR-H2 comprising the amino acid sequence of SEQ ID NO:47.

5. The anti-CLL-1 antibody of claim 4 , wherein the CLL-1 binding domain comprises HVR-H2 comprising the amino acid sequence of SEQ ID NO:11.

6. The anti-CLL-1 antibody of claim 4 , wherein the CLL-1 binding domain comprises HVR-H2 comprising the amino acid sequence of SEQ ID NO:43.

7. The anti-CLL-1 antibody of claim 4 , wherein the CLL-1 binding domain comprises HVR-H2 comprising the amino acid sequence of SEQ ID NO:44.

8. The anti-CLL-1 antibody of claim 2 , wherein the antibody comprises a CLL-1 binding domain comprising:
a) a heavy chain variable region comprising the sequence of SEQ ID NO:33 and a light chain variable region comprising the sequence of SEQ ID NO:32;
b) a heavy chain variable region comprising the sequence of SEQ ID NO:34 and a light chain variable region comprising the sequence of SEQ ID NO:32;
c) a heavy chain variable region comprising the sequence of SEQ ID NO:46 and a light chain variable region comprising the sequence of SEQ ID NO:32; or
d) a heavy chain variable region comprising the sequence of SEQ ID NO:48 and a light chain variable region comprising the sequence of SEQ ID NO:32.

9. The anti-CLL-1 antibody of claim 1 , wherein the CLL-1 binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:18; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:19; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:20.

10. The anti-CLL-1 antibody of claim 9 , wherein the antibody comprises a CLL-1 binding domain comprising: (a) a heavy chain variable region comprising the sequence of SEQ ID NO:40 and (b) a light chain variable region comprising the sequence of SEQ ID NO:39.

11. The anti-CLL-1 antibody of claim 1 , wherein the antibody comprises a CLL-1 binding domain having one or more of the following characteristics:
a. binds to recombinant human CLL-1;
b. binds to recombinant cynomolgus monkey CLL-1;
c. binds to endogenous CLL-1 on the surface of human peripheral blood mononucleocytes (PBMCs);
d. binds to endogenous CLL-1 on the surface of cynomolgus monkey PBMCs;
e. binds to endogenous CLL-1 on the surface of a cancer cell;
f. binds to endogenous CLL-1 on the surface of an AML cancer cell;
g. binds to endogenous CLL-1 on the surface of HL-60 cells;
h. binds to endogenous CLL-1 on the surface of EOL-1 cells;
i. binds to CLL-1 comprising a K244Q mutation;
j. competes for human CLL-1 binding with R&D clone 687317 antibody;
k. binds to endogenous human CLL-1 with a Kd of less than 15 nM;
l. binds to recombinant human CLL-1 with a Kd of less than 10 nM; and/or
m. binds to recombinant cynomolgus monkey CLL-1 with a Kd of less than 10 nM.

12. The anti-CLL-1 antibody of claim 1 , wherein the CD3 binding domain binds a CD3 epitope comprising and/or consisting of Gln1, Asp2, Glu6, and Met7 of human CD3c polypeptide.

13. The anti-CLL-1 antibody of claim 1 , wherein the CD3 binding domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:71; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:72; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:73; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 74; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:75; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:76.

14. The anti-CLL-1 antibody of claim 1 , wherein the CD3 binding domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:77; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:78; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:79; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 74; (e)

Assignees

• Genentech Inc

Inventors

• Kelley Robert F
• Leong Steven R
• Liang Wei-Ching
• Mathieu Mary
• Polson Andrew G
• Zheng Bing
• Chen Xiaocheng
• Chiu Cecilia Pui Chi
• Dennis Mark S
• Ebens Allen
• Wu Yan

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/526

  CH3 domain · CPC title