US 10,307,455 B2 · Activin type 2 receptor antibodies

Abstract

This disclosure provides ActRII-binding proteins such as anti-ActRIIA and anti-ActRIIB antibodies, and compositions and methods for making the ActRII-binding proteins. In certain aspects the ActRII-binding proteins inhibit, or antagonize ActRII activity. In addition, the disclosure provides compositions and methods for diagnosing and treating diseases and conditions associated muscle wasting; a fibrotic condition; an inflammatory, cardiovascular, pulmonary, musculoskeletal, neurologic, ocular, skeletal, autoimmune, or metabolic disease or condition; wound healing; and cancer, and other ActRII-mediated diseases and conditions.

An ActRII-binding antibody comprising a set of CDRs in which:

(a) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:166;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:167;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:168;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:173;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:174;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:175;
and wherein the antibody binds ActRIIB;
(b) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
3 or 17;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
4 or 18;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
5;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
10;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
11;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
12;
and wherein the antibody binds ActRIIB;
(c) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
64 or 78;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
65 or 79;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
66 or 80;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
71;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
72;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:73;
and wherein the antibody binds ActRIIB;
(d) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
3 or 58;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
4 or 59;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
46;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
51;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
52;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
53;
and wherein the antibody binds ActRIIB;
(e) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
145;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
146;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
147;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
152;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
153;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
154;
and wherein the antibody binds ActRIIB;
(f) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
85 or 99;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
86 or 100;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
87 or 101;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(g) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
126;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
127;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
128;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
133;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
134;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
135;
and wherein the antibody binds ActRIIA;
h) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
3 or 17;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
24 or 30;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
5:
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
10;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
11;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
12;
and wherein the antibody binds ActRIIB;
(i) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
3 or 17;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
36;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
5;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
10;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
11;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
12;
and wherein the antibody binds ActRIIB;
(j) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
23 or 29;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
4 or 18;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
5;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
10;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
11;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
12;
and wherein the antibody binds ActRIIB;
(k) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
23 or 29;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
24 or 30;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
5;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
10;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
11;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
12;
and wherein the antibody binds ActRIIB;
(l) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
23 or 29;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
36;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
5;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
10;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
11;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
12;
and wherein the antibody binds ActRIIB:
(m) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
35 or 41;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
4 or 18;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
5;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
10;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
11;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
12;
and wherein the antibody binds ActRIIB:
(n) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
35 or 41;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
24 or 30;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
5;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
10;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
11;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
12;
and wherein the antibody binds ActRIIB;
(o) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
35 or 41;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
36;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
5;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
10;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
11;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
12;
and wherein the antibody binds ActRIIB;
(p) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
85 or 99;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
86 or 100;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
108 or 115
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(g) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
85 or 99;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
86 or 100;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
121;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(r) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
85 or 99;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
107 or 114;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
87 or 101;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(s) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
85 or 99;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
107 or 114;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
108 or 115;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(t) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
85 or 99;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
107 or 114;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
121;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(u) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
85 or 99;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
120;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
87 or 101;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(v) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
85 or 99;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
120;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
108 or 115;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(w) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
85 or 99;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
120;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
121;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(x) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
106 or 113;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
86 or 100;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
87 or 101;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(y) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
106 or 113;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
86 or 100;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
108 or 115;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(z) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
106 or 113;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
86 or 100;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
121;
(iv) VL-CDR has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(aa) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
106 or 113;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
107 or 114;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
87 or 101;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(bb) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
106 or 113;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
107 or 114;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
108 or 115;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(cc) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
106 or 113;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
107 or 114;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
121;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(dd) (i) VH-CDRI has the amino acid sequence of SEQ ID NO:
106 or 113;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
120;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
87 or 101;
(iv) VL-CDRI has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(ee) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
106 or 113;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
120;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
108 or 115;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA;
(ff) (i) VH-CDR1 has the amino acid sequence of SEQ ID NO:
106 or 113;
(ii) VH-CDR2 has the amino acid sequence of SEQ ID NO:
120;
(iii) VH-CDR3 has the amino acid sequence of SEQ ID NO:
121;
(iv) VL-CDR1 has the amino acid sequence of SEQ ID NO:
92;
(v) VL-CDR2 has the amino acid sequence of SEQ ID NO:
93;
and
(vi) VL-CDR3 has the amino acid sequence of SEQ ID NO:
94;
and wherein the antibody binds ActRIIB and ActRIIA.

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Activin type 2 receptor antibodies

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Activin type 2 receptor antibodies

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Abstract

Claims14