Anti-ACTH antibodies and use thereof
The present invention is directed to antibodies and fragments thereof having binding specificity for ACTH. Another embodiment of this invention relates to the antibodies binding fragments thereof described herein, comprising the sequences of the V H , V L and/or CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-ACTH antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention further contemplates methods of making said anti-ACTH antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-ACTH antibodies and binding fragments thereof for the diagnosis, assessment, prevention and treatment of diseases and disorders associated with ACTH, such as Cushing's Disease, Cushing's Syndrome, Parkinson's disease, obesity, diabetes, sleep disorders depression, anxiety disorders, cancer, muscle atrophy, hypertension, hyperinsulinemia, cognitive dysfunction, Alzheimer's disease, galactorrhea, stress related conditions, cardiac conditions, metabolic syndrome, hyperaldosteronism, Conn's syndrome and familial hyperaldosteronism.
1. An anti-human adrenocorticotrophic hormone (ACTH) antibody, or antigen-binding fragment thereof, comprising three heavy- and three light-chain complementarity-determining regions (CDRs) selected from:
(a) the Ab1 heavy- and light-chain CDRs of SEQ ID NOs: 4, 6, 8, 24, 26, and 28;
(b) the Ab2 heavy- and light-chain CDRs of SEQ ID NOs: 44, 46, 48, 64, 66, and 68;
(c) the Ab3 heavy- and light-chain CDRs of SEQ ID NOs: 84, 86, 88, 104, 106, and 108;
(d) the Ab4 heavy- and light-chain CDRs of SEQ ID NOs: 124, 126, 128, 144, 146, and 148;
(e) the Ab10 heavy- and light-chain CDRs of SEQ ID NOs: 324, 326, 328, 344, 346, and 348;
(f) the Ab11 heavy- and light-chain CDRs of SEQ ID NOs: 364, 366, 368, 384, 386, and 388;
(g) the Ab12 heavy- and light-chain CDRs of SEQ ID NOs: 404, 406, 408, 424, 426, and 428;
(h) the Ab1.H heavy- and light-chain CDRs of SEQ ID NOs:444, 446, 448, 464, 466, and 468;
(i) the Ab2.H heavy- and light-chain CDRs of SEQ ID NOs: 484, 486, 488, 504, 506, and 508;
(j) the Ab3.H heavy- and light-chain CDRs of SEQ ID NOs: 524, 526, 528, 544, 546 and 548;
(k) the Ab4.H heavy- and light-chain CDRs of SEQ ID NOs: 564, 566, 568, 584, 586, and 588;
(l) the Ab11.H heavy- and light-chain CDRs of SEQ ID NOs: 764, 766, 768, 784, 786, and 788;
(m) the Ab11A.H heavy- and light-chain CDRs of SEQ ID NOs: 804, 806, 808, 824, 826, and 828; and
(n) the Ab12.H heavy- and light-chain CDRs of SEQ ID NOs: 844, 846, 848, 864, 866, and 868.
2. The anti-human ACTH antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or fragment comprises variable heavy- and light-chains that, respectively:
(i) have at least 90% identity to SEQ ID NOs: 2 and 22, and contain the CDRs according to (a);
(ii) have at least 90% identity to SEQ ID NOs: 42 and 62, and contain the CDRs according to (b);
(iii) have at least 90% identity to SEQ ID NOs: 82 and 102, and contain the CDRs according to (c);
(iv) have at least 90% identity to SEQ ID NOs: 122 and 142, and contain the CDRs according to (d);
(v) have at least 90% identity to SEQ ID NOs: 322 and 342, and contain the CDRs according to (e);
(vi) have at least 90% identity to SEQ ID NOs: 362 and 382, and contain the CDRs according to (f);
(vii) have at least 90% identity to SEQ ID NOs: 402 and 422, and contain the CDRs according to (g);
(viii) have at least 90% identity to SEQ ID NOs: 442 and 462, and contain the CDRs according to (h);
(ix) have at least 90% identity to SEQ ID NOs: 482 and 502, and contain the CDRs according to (i);
(x) have at least 90% identity to SEQ ID NOs: 522 and 542, and contain the CDRs according to (g);
(xi) have at least 90% identity to SEQ ID NOs: 562 and 582, and contain the CDRs according to (k);
(xii) have at least 90% identity to SEQ ID NOs: 762 and 782, and contain the CDRs according to (l);
(xiii) have at least 90% identity to SEQ ID NOs: 802 and 822, and contain the CDRs according to (m); or (xiv) have at least 90% identity to SEQ ID NOs: 842 and 862, and contain the CDRs according to (n).
3. The anti-human ACTH antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or fragment comprises the variable heavy- and light-chains of:
(i) SEQ ID NOs: 2 and 22;
(ii) SEQ ID NOs: 42 and 62;
(iii) SEQ ID NOs: 82 and 102;
(iv) SEQ ID NOs: 122 and 142;
(v) SEQ ID NOs: 322 and 342;
(vi) SEQ ID NOs: 362 and 382;
(vii) SEQ ID NOs: 402 and 422;
(viii) SEQ ID NOs: 442 and 462;
(ix) SEQ ID NOs: 482 and 502;
(x) SEQ ID NOs: 522 and 542;
(xi) SEQ ID NOs: 562 and 582;
(xii)SEQ ID NOs: 762 and 782;
(xiii) SEQ ID NOs: 802 and 822; or
(xiv) SEQ ID NOs: 842 and 862.
4. The anti-human ACTH antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody or fragment comprises an scFv, Fab fragment, Fab′ fragment, or F(ab′) 2 fragment.
5. The anti-human ACTH antibody or antigen-binding fragment thereof of claim 1 , wherein said antibody comprises an IgG1, IgG2, IgG3, or IgG4 constant domain.
6. The anti-human ACTH antibody or antigen-binding fragment thereof of claim 5 , wherein said constant region that has been modified to alter at least one of effector function, half-life, proteolysis, or glycosylation.
7. The anti-human ACTH antibody or antigen-binding fragment thereof of claim 5 , wherein said constant region is an IgG1 constant region.
8. The anti-human ACTH antibody or antigen-binding fragment thereof of claim 7 , wherein said IgG1 constant region comprises an IgG1 heavy chain constant domain polypeptide having a sequence selected from SEQ ID NO: 886, 887, or 888.