CD47 antigen-binding molecules
CD47 antigen-binding molecules are disclosed. Also disclosed are nucleic acids and expression vectors encoding, compositions comprising, and methods using, the CD47 antigen-binding molecules.
1. An antigen-binding molecule which binds to CD47, comprising:
(a)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:137
HC-CDR2 having the amino acid sequence of SEQ ID NO:138
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:32
LC-CDR2 having the amino acid sequence of SEQ ID NO:33
LC-CDR3 having the amino acid sequence of SEQ ID NO:34
or
(b)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:24
HC-CDR2 having the amino acid sequence of SEQ ID NO:25
HC-CDR3 having the amino acid sequence of SEQ ID NO:26 and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:32
LC-CDR2 having the amino acid sequence of SEQ ID NO:33
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(c)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:24
HC-CDR2 having the amino acid sequence of SEQ ID NO:25
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:139
LC-CDR2 having the amino acid sequence of SEQ ID NO:141
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(d)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:137
HC-CDR2 having the amino acid sequence of SEQ ID NO:138
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:139
LC-CDR2 having the amino acid sequence of SEQ ID NO:141
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(e)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:24
HC-CDR2 having the amino acid sequence of SEQ ID NO:25
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:140
LC-CDR2 having the amino acid sequence of SEQ ID NO:141
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(f)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:137
HC-CDR2 having the amino acid sequence of SEQ ID NO:138
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:140
LC-CDR2 having the amino acid sequence of SEQ ID NO:141
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(g)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:137
HC-CDR2 having the amino acid sequence of SEQ ID NO:138
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:32
LC-CDR2 having the amino acid sequence of SEQ ID NO:141
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(h)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:137
HC-CDR2 having the amino acid sequence of SEQ ID NO:138
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:32
LC-CDR2 having the amino acid sequence of SEQ ID NO:33
LC-CDR3 having the amino acid sequence of SEQ ID NO:142.
2. The antigen-binding molecule according to claim 1 , wherein the antigen-binding molecule comprises:
a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132, 23, 39, 127, 129, 130 or 131; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128, 31, 44, 133, 134, 135 or 136.
3. The antigen-binding molecule according to claim 1 , wherein the antigen-binding molecule comprises:
(i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128;
or
(ii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:23; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:31;
or
(iii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:39; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:44;
a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:127; and
(iv) a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128;
or
(v) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:129; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128;
or
(vi) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:130; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128;
or
(vii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:131; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128;
or
(viii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:131; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:133;
or
(ix) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:133;
or
(x) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:131; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:134;
or
(xi) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:134;
or
(xii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:135;
or
(xiii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:136.
4. The antigen-binding molecule according to claim 1 , wherein the antigen-binding molecule inhibits interaction between CD47 and SIRPα.
5. The antigen-binding molecule according to claim 1 , wherein the antigen-binding molecule is a multispecific antigen-binding molecule, and further comprises an antigen-binding domain specific for a target antigen other than CD47.
6. A method of treating a cancer in a subject, comprising administering to the subject a therapeutically effective amount of an antigen-binding molecule which binds to CD47and comprises:
(a)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:137
HC-CDR2 having the amino acid sequence of SEQ ID NO:138
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:32
LC-CDR2 having the amino acid sequence of SEQ ID NO:33
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(b)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:24
HC-CDR2 having the amino acid sequence of SEQ ID NO:25
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:32
LC-CDR2 having the amino acid sequence of SEQ ID NO:33
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(c)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:24
HC-CDR2 having the amino acid sequence of SEQ ID NO:25
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:139
LC-CDR2 having the amino acid sequence of SEQ ID NO:141
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(d)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:137
HC-CDR2 having the amino acid sequence of SEQ ID NO:138
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:139
LC-CDR2 having the amino acid sequence of SEQ ID NO:141
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(e)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:24
HC-CDR2 having the amino acid sequence of SEQ ID NO:25
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:140
LC-CDR2 having the amino acid sequence of SEQ ID NO:141
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(f)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:137
HC-CDR2 having the amino acid sequence of SEQ ID NO:138
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:140
LC-CDR2 having the amino acid sequence of SEQ ID NO:141
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(g)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:137
HC-CDR2 having the amino acid sequence of SEQ ID NO:138
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:32
LC-CDR2 having the amino acid sequence of SEQ ID NO:141
LC-CDR3 having the amino acid sequence of SEQ ID NO:34;
or
(h)
(i) a heavy chain variable (VH) region incorporating the following CDRs:
HC-CDR1 having the amino acid sequence of SEQ ID NO:137
HC-CDR2 having the amino acid sequence of SEQ ID NO:138
HC-CDR3 having the amino acid sequence of SEQ ID NO:26; and
(ii) a light chain variable (VL) region incorporating the following CDRs:
LC-CDR1 having the amino acid sequence of SEQ ID NO:32
LC-CDR2 having the amino acid sequence of SEQ ID NO:33
LC-CDR3 having the amino acid sequence of SEQ ID NO:142.
7. The method according to claim 6 , wherein the antigen-binding molecule comprises:
a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132, 23, 39, 127, 129, 130 or 131; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128, 31, 44, 133, 134, 135 or 136.
8. The method according to claim 6 , wherein the antigen-binding molecule comprises:
(i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128;
or
(ii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:23; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:31;
or
(iii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:39; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:44;
or
(iv)
a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:127; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128;
or
(v) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:129; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128;
or
(vi) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:130; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128;
or
(vii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:131; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:128;
or
(viii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:131; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:133;
or
(ix) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:133;
or
(x) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:131; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:134;
or
(xi) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:134;
or
(xii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:135;
or
(xiii) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:132; and
a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:136.
9. The method according to claim 6 , wherein the antigen-binding molecule inhibits interaction between CD47 and SIRPα.
10. The method according to claim 6 , wherein the antigen-binding molecule is a multispecific antigen-binding molecule, and further comprises an antigen-binding domain specific for a target antigen other than CD47.
11. The method according to claim 6 , wherein the cancer is selected from: a hematologic malignancy, a myeloid hematologic malignancy, a lymphoblastic hematologic malignancy, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), bladder cancer, brain cancer, glioblastoma, ovarian cancer, breast cancer, colon cancer, liver cancer, hepatocellular carcinoma, prostate cancer, lung cancer, Non-small Cell Lung Cancer (NSCLC), skin cancer and melanoma.