NEUTRALIZING PROLACTIN RECEPTOR ANTIBODIES AND THEIR THERAPEUTIC USE
The present invention is directed to pharmaceutical compositions containing one or more neutralizing prolactin receptor antibodies and antigen binding fragments, and their use in the treatment or prevention of benign disorders and indications mediated by the prolactin receptor such as endometriosis, adenomyosis, non-hormonal female contraception, benign breast disease and mastalgia, lactation inhibition, benign prostate hyperplasia, fibroids, hyper- and normoprolactinemic hair loss, and cotreatment in combined hormone therapy to inhibit mammary epithelial cell proliferation. The composition of the invention blocks prolactin receptor-mediated signaling.
1 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an antibody or antigen-binding fragment thereof, whereby the antibody competes to the antibodies 006-H08, 005-C04, 002-H06, 002-H08, 006-H07, or 001-E06 for binding to the epitopes of the extracellular domain of the prolactin receptor and human polymorphic variants thereof, and whereby the amino acid sequence of the extracellular domain of the prolactin receptor corresponds to SEQ ID NO: 70, and the nucleic acid sequence corresponds to SEQ ID NO: 71, and whereby the composition antagonizes prolactin receptor mediated signaling.
2 . Pharmaceutical composition according to claim 1 ,
a. whereby the amino acid sequences of the variable heavy and light regions are at least 60%, or more preferred 70%, or 80%, still more preferred at least 90% and most preferred at least 95% identical to the sequences of the antibodies 006-H08, 005-C04, 002-H06, 002-H08, 006-H07, or 001-E06 according to table 5, or
b. whereby the amino acid sequences of the CDR regions are at least 60%, or more preferred 70%, or 80%, still more preferred at least 90% and most preferred at least 95% identical to the sequences of the antibodies 006-H08, 005-C04, 002-H06, 002-H08, 006-H07, or 001-E06 according to table 5.
3 . A pharmaceutical composition according to claim 2 , whereby
a. the variable heavy chain contains the CDR sequences corresponding to SEQ ID NO: 1, 7 and 13 and the variable light chain contains the CDR sequences corresponding to SEQ ID NO: 18, 24, and 29; or
b. the variable heavy chain contains the CDR sequences corresponding to SEQ ID NO: 2, 8 and 13 and the variable light chain contains the CDR sequences corresponding to SEQ ID NO: 19, 25, and 30; or
c. the variable heavy chain contains the CDR sequences corresponding to SEQ ID NO: 3, 9 and 14 and the variable light chain contains the CDR sequences corresponding to SEQ ID NO: 20, 24, and 31; or
d. the variable heavy chain contains the CDR sequences corresponding to SEQ ID NO: 4, 10 and 15 and the variable light chain contains CDR sequences corresponding to SEQ ID NO: 21, 26, and 32; or
e. the variable heavy chain contains the CDR sequences corresponding to SEQ ID NO: 5, 11 and 16 and the variable light chain contains the CDR sequences corresponding to SEQ ID NO: 22, 27, and 30; or
f. the variable heavy chain contains the CDR sequences corresponding to SEQ ID NO: 6, 12 and 17 and the variable light chain contains the CDR sequences corresponding to SEQ ID NO: 23, 28, and 33.
4 . Pharmaceutical composition according to claims 1 to 3 , whereby the antibody
a. 006-H08 comprises a variable heavy region corresponding to a nucleic acid sequence according to SEQ ID NO: 46 an amino acid sequence according to SEQ ID NO: 34; and a variable light region with a nucleic acid sequence according to SEQ ID NO: 52, and an amino acid sequence according to SEQ ID NO: 40,
b. 002-H06 comprises an antibody having a variable heavy region corresponding to a nucleic acid sequence according to SEQ ID NO: 47, an amino acid sequence according to SEQ ID NO: 35; and a variable light region with a nucleic acid sequence according to SEQ ID NO: 53, and an amino acid sequence according to SEQ ID NO: 41,
c. 002-H08 comprises an antibody having a variable heavy region corresponding to a nucleic acid sequence according to SEQ ID NO: 48, an amino acid sequence according to SEQ ID NO: 36; and a variable light region with a nucleic acid sequence according to SEQ ID NO: 54, and an amino acid sequence according to SEQ ID NO: 42,
d. 006-H07 comprises an antibody having a variable heavy region corresponding to a nucleic acid sequence according to SEQ ID NO: 49, an amino acid sequence according to SEQ ID NO: 37; and a variable light region with a nucleic acid sequence according to SEQ ID NO: 55, and an amino acid sequence according to SEQ ID NO: 43,
e. 001-E06 comprises an antibody having a variable heavy region corresponding to a nucleic acid sequence according to SEQ ID NO: 50 an amino acid sequence according to SEQ ID NO: 38; and a variable light region with a nucleic acid sequence according to SEQ ID NO: 56, and an amino acid sequence according to SEQ ID NO: 44, and
f. 005-C04 comprises an antibody having a variable heavy region corresponding to a nucleic acid sequence according to SEQ ID NO: 51 an amino acid sequence according to SEQ ID NO: 39; and a variable light region with a nucleic acid sequence according to SEQ ID NO: 57, and an amino acid sequence according to SEQ ID NO: 45.
5 - 8 . (canceled)
9 . A pharmaceutical composition according to claim 1 further comprising at least one other agent.
10 - 25 . (canceled)
26 . A pharmaceutical composition according to claim 1 , further comprising an estrogen.
27 . A pharmaceutical composition according to claim 2 further comprising at least one other agent.
28 . A pharmaceutical composition according to claim 2 further comprising an estrogen.
29 . A method for treating or preventing endometriosis, adenomyosis (endometriosis interna), hot flashes, benign breast disease, mastalgia, benign prostate hyperplasia, hyper- and normoprolactinemic hair loss comprising the step of administering to a patient in need thereof an antibody according to claim 1 .
30 . A method of contraception or for preventing pregnancy comprising the step of administering to a patient in need thereof an antibody according to claim 1 .
31 . A method for inhibition of lactation comprising the step of administering to a patient in need thereof an antibody according to claim 1 .
32 . A method for treating or preventing endometriosis, adenomyosis (endometriosis interna), hot flashes, benign breast disease, mastalgia, benign prostate hyperplasia, hyper- and normoprolactinemic hair loss comprising the step of administering to a patient in need thereof an antibody according to claim 2 .
33 . A method of contraception or for preventing pregnancy comprising the step of administering to a patient in need thereof an antibody according to claim 2 .
34 . A method for inhibition of lactation comprising the step of administering to a patient in need thereof an antibody according to claim 2 .