Prlr-specific antibody and uses thereof

An antibody that comprises 1, 2, 3, 4, 5 or 6 CDRs of any of antibodies chXHA.06.642, chXHA.06.275, he.06.642-1, he.06.642-2, he.06.275-1, he.06.275-2, he.06.275-3, he.06.275-4, XPA.06.128, XPA.06.129, XPA.06.130, XPA.06.131, XPA.06.141, XPA.06.147, XPA.06.148, XPA.06.158, XPA.06.159, XPA.06.163, XPA.06.167, XPA.06.171, XPA.06.178, XPA.06.181, XPA.06.192, XPA.06.202, XPA.06.203, XPA.06.206, XPA.06.207, XPA.06.210, XPA.06.212, XPA.06.217, XPA.06.219, XPA.06.229, XPA.06.233, XPA.06.235, XPA.06.239, XPA.06.145, XHA.06.567, XHA.06.642, XHA.06.983, XHA.06.275, XHA.06.189, or XHA.06.907.

The antibody of any of the preceding claims in which at least one amino acid within a CDR is substituted by a corresponding residue of a corresponding CDR of another anti-PRLR antibody.

The antibody of any of the preceding claims in which one or two amino acids within a CDR have been modified.

The antibody of any of the preceding claims that retains at least 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity over either the variable light or heavy region to the antibodies of chXHA.06.642, chXHA.06.275, he.06.642-1, he.06.642-2, he.06.275-1, he.06.275-2, he.06.275-3, he.06.275-4, XPA.06.128, XPA.06.129, XPA.06.130, XPA.06.131, XPA.06.141, XPA.06.147, XPA.06.148, XPA.06.158, XPA.06.159, XPA.06.163, XPA.06.167, XPA.06.171, XPA.06.178, XPA.06.181, XPA.06.192, XPA.06.202, XPA.06.203, XPA.06.206, XPA.06.207, XPA.06.210, XPA.06.212, XPA.06.217, XPA.06.219, XPA.06.229, XPA.06.233, XPA.06.235, XPA.06.239, XPA.06.145, XHA.06.567, XHA.06.642, XHA.06.983, XHA.06.275, XHA.06.189, or XHA.06.907.

The antibody of any of the preceding claims that comprises a constant region of a human antibody sequence and one or more heavy and light chain variable framework regions of a human antibody sequence.

The antibody of any of the preceding claims wherein the heavy chain constant region is a modified or unmodified IgG, IgM, IgA, IgD, IgE, a fragment thereof, or combinations thereof.

The antibody of any of the preceding claims that has an equilibrium dissociation constant of 10−6, 10−7, 10−8 or 10−9 M or lower to PRLR.

The antibody of any of the preceding claims comprising a conservative substitution in the CDRs.

The antibody of any of the preceding claims comprising a conservative or non-conservative change in low and moderate risk residues.

The antibody of any of the preceding claims wherein the light chain constant region is a modified or unmodified lambda light chain constant region, a kappa light chain constant region, a fragment thereof, or combinations thereof.

The antibody of any of the preceding claims that inhibits PRLR dimerization.

The antibody of any of the preceding claims that inhibits PRLR intracellular phosphorylation.

The antibody of any of the preceding claims that inhibits the induction of MAPK phosphorylation.

The antibody of any of the preceding claims that inhibits the induction of Stat5 phosphorylation.

The antibody of any of the preceding claims that inhibits the induction of AKT phosphorylation.

The antibody of any of the preceding claims that inhibits the binding of PRL to PRLR.

The antibody of any of the preceding claims that inhibits VEGF production and/or angiogenesis.

The antibody of any of the preceding claims that inhibits the proliferation of a cancer cell.

The antibody of any of the preceding claims that is conjugated to another diagnostic or therapeutic agent.

A method of screening for an antibody to the extracellular domain of a PRLR protein useful for the treatment of cancer comprising the steps of:

• contacting a polypeptide comprising the ECD of PRLR with a candidate antibody that contains at least 1, 2, 3, 4, 5, or 6 CDRs of antibodies chXHA.06.642, chXHA.06.275, he.06.642-1, he.06.642-2, he.06.275-1, he.06.275-2, he.06.275-3, he.06.275-4, XPA.06.128, XPA.06.129, XPA.06.130, XPA.06.131, XPA.06.141, XPA.06.147, XPA.06.148, XPA.06.158, XPA.06.159, XPA.06.163, XPA.06.167, XPA.06.171, XPA.06.178, XPA.06.181, XPA.06.192, XPA.06.202, XPA.06.203, XPA.06.206, XPA.06.207, XPA.06.210, XPA.06.212, XPA.06.217, XPA.06.219, XPA.06.229, XPA.06.233, XPA.06.235, XPA.06.239, XPA.06.145, XHA.06.567, XHA.06.642, XHA.06.983, XHA.06.275, XHA.06.189, and XHA.06.907;
• detecting binding affinity of the candidate antibody to the polypeptide, and
• identifying said candidate antibody as an antibody useful for the treatment of cancer if an equilibrium dissociation constant of 10−6 M or lower is detected.

A method of treating a subject suffering from cancer comprising the step of administering an antibody of any of the preceding claims in a therapeutically effective amount.

A method of targeting a tumor cell expressing PRLR comprising the step of administering an antibody of any of the preceding claims, conjugated to a radionuclide or other toxin.

A kit comprising an antibody of any of the preceding claims comprising a therapeutically effective amount of an antibody of the invention, packaged in a container, said kit optionally containing a second therapeutic agent, and further comprising a label attached to or packaged with the container, the label describing the contents of the container and providing indications and/or instructions regarding use of the contents of the container to treat cancer.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence selected from the group consisting of SEQ ID NO:

• 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 82, 84, 86, 88, 91, 95 and 96.

An antibody that binds the extracellular domain of PRLR with comprising a variable heavy chain amino acid sequence selected from the group consisting of SEQ ID NO:

• 20, 2, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 83, 85, 87, 89, 90, 93, 94, 97 and 98.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence SEQ ID NO:

• 88, and a variable heavy chain amino acid sequence of SEQ ID NO:
• 89.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence SEQ ID NO:

• 88, and a variable heavy chain amino acid sequence of SEQ ID NO:
• 90.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence of SEQ ID NO:

• 91, and a variable heavy chain amino acid sequence of SEQ ID NO:
• 93.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence of SEQ ID NO:

• 91, and a variable heavy chain amino acid sequence of SEQ ID NO:
• 94.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence of SEQ ID NO:

• 92, and a variable heavy chain amino acid sequence of SEQ ID NO:
• 93.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence of SEQ ID NO:

• 92, and a variable heavy chain amino acid sequence of SEQ ID NO:
• 94.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence of SEQ ID NO:

• 95, and a variable heavy chain amino acid sequence of SEQ ID NO:
• 97.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence of SEQ ID NO:

• 95, and a variable heavy chain amino acid sequence of SEQ ID NO:
• 98.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence of SEQ ID NO:

• 96, and a variable heavy chain amino acid sequence of SEQ ID NO:
• 97.

An antibody that binds the extracellular domain of PRLR comprising a variable light chain amino acid sequence of SEQ ID NO:

• 96, and a variable heavy chain amino acid sequence of SEQ ID NO:
• 98.

An antibody that binds the extracellular domain of human PRLR with an equilibrium dissociation constant (KD) of at least 10,000 to 15,000 fold lower than the extracellular domain of murine PRLR.

An antibody that binds the extracellular domain of human PRLR, the extracellular domain of murine PRLR, and the extracellular domain of rat PRLR

An antibody that binds the extracellular domain of human, murine and rat PRLR with an equilibrium dissociation constant (KD) of 10−6 M or lower.