NEUTRALIZING PROLACTIN RECEPTOR ANTIBODIES AND THEIR THERAPEUTIC USE
The present invention is directed to the neutralizing prolactin receptor antibody 006-H07, and antigen binding fragments, pharmaceutical compositions containing them 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 antibodies of the invention block prolactin receptor-mediated signaling.
1 - 2 . (canceled)
3 . Antibody which binds to epitopes of the extracellular domain of the prolactin receptor and human polymorphic variants thereof, 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, whereby the antibody or the antigen-binding fragment competes to the antibody 006-H07.
4 . Antibody or antigen-binding fragment according to claim 3 ,
a. whereby the amino acid sequences of the variable heavy and light regions are at least 60%, more preferred 70%, more preferred 80%, or 90%, or even more preferred 95% identical to SEQ ID NO: 37 for the variable heavy chain domain and, identical to SEQ ID NO: 43 for the variable light chain domain, or
b. whereby the amino acid sequences of the CDRs are at least 60%, more preferred 70%, more preferred 80%, more preferred 90%, or even more preferred 95% identical to SEQ ID NO: 4, 10, and 15 for the heavy chain domain, and to SEQ ID NO: 21, 26, and 32 for the variable light chain domain.
5 . Antibody or antigen-binding fragment comprising the CDRs of the antibody of claim 3 , whereby the variable heavy chain contains the CDR sequences corresponding to SEQ ID NO: 4 (HCDR1), 10 (HCDR2), and 15 (HCDR3), and the variable light chain contains the CDR sequences corresponding to SEQ ID NO: 21 (LCDR1), 26 (LCDR2), and 32 (LCDR3).
6 . Antibody or antigen-binding fragment according to claim 3 , whereby the antibody 006-H07 comprises a variable heavy chain domain corresponding to a nucleic acid sequence according to SEQ ID NO: 49, and an amino acid sequence according to SEQ ID NO: 37, and a variable light chain domain with a nucleic acid sequence according to SEQ ID NO: 55, and an amino acid sequence according to SEQ ID NO: 43.
7 . Antibody or antigen-binding fragment according to claim 3 , whereby the antibody contains one, two, three, four, five or six of the CDRs corresponding to SEQ ID NO: 4, 10, 15, 21, 26, and 32.
8 . Antibody according to claim 3 , whereby the antibody consists of an antigen-binding region that binds specifically to or has a high affinity of for one or more regions of PRLR, whose amino acid sequence is depicted by SEQ ID NO: 70 and human polymorphic variants of SEQ ID NO: 70, amino acid position 1 to 210, whereby the affinity is at least 100 nM, preferably less than about 100 nM, more preferably less than about 30 nM, even more preferred with an affinity of less than about 10 nM, or even more preferred with an affinity of less than 1 nM.
9 . Antibody of claim 3 wherein the heavy constant is a modified or unmodified IgG1, IgG2, IgG3 or IgG4.
10 . An isolated nucleic acid sequence encoding an antibody or antigen-binding fragment according to claim 3 .
11 . An isolated nucleic acid sequence according to claim 10 , whereby the nucleic acid sequences are according to table 5.
12 . Expression vector comprising a nucleic acid sequence of claim 10 .
13 . Host cell comprising the vector of claim 12 , whereby the host cell can be a higher eukaryotic host cell, such as a mammalian cell, a lower eukaryotic host cell, such as a yeast cell, and may be a prokaryotic cell, such as a bacterial cell.
14 . A method of producing an antibody or antigen-binding fragment, comprising culturing the host cell of claim 13 under suitable conditions and recovering said antibody.
15 - 36 . (canceled)
37 . 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 3 .
38 . A method of contraception or for preventing pregnancy comprising the step of administering to a patient in need thereof an antibody according to claim 3 .
39 . A method for inhibition of lactation comprising the step of administering to a patient in need thereof an antibody according to claim 3 .