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Discovery and characterization of prolactin neutralizing monoclonal antibodies for the treatment of female-prevalent pain disorders
Prolactin (PRL) has recently been demonstrated to elicit female-selective nociceptor sensitization and increase pain-like behaviors in female animals. Here we report the discovery and characterization of first-in-class, humanized PRL neutralizing monoclonal antibodies (PRL mAbs). We obtained two potent and selective PRL mAbs, PL 200,031 and PL 200,039. PL 200,031 was engineered as human IgG1 whereas PL 200,039 was reformatted as human IgG4. Both mAbs have sub-nanomolar affinity for human PRL (hPRL) and produce concentration-dependent and complete inhibition of hPRL signaling at the hPRL receptor (hPRLR). These two PRL mAbs are selective for hPRL as they do not inhibit other hPRLR agonists such as human growth hormone or placental lactogen. They also cross-react with non-human primate PRL but not with rodent PRL. Further, both mAbs show long clearance half-lives after intravenous administration in FcRn-humanized mice. Consistent with their isotypes, these mAbs only differ in binding affinities to Fcγ receptors, as expected by design. Finally, PL 200,019, the murine parental mAb of PL 200,031 and PL 200,039, fully blocked stress-induced and PRL-dependent pain behaviors in female PRL-humanized mice, thereby providing in vivo preclinical proof-of-efficacy for PRL mAbs in mechanisms relevant to pain in females.
Topics: Monoclonal Publications Prolactin
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Generation of Neutralizing Human Monoclonal Antibodies Against a Therapeutic Target from the Alloy Therapeutics Mouse
Immunization of transgenic animals producing human antibodies is the most successful approach to obtaining fully human therapeutic antibodies. They allow for the rapid generation of candidate antibodies and the ability to transition lead candidates to clinical development without undergoing time-consuming steps such as the humanization of murine antibodies or the affinity maturation of antibodies from structural display libraries.
Topics: Posters Monoclonal ATX-GX Alloy Therapeutics
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A Rapid, High-Throughput Recombinant Antibody Expression System for Therapeutic Antibody Discovery and Validation
Hybridoma cell lines have historically offered an efficient, low-cost means to produce large numbers of monoclonal antibodies. However, there are reasons that warrant recombinantly expressing an antibody at a preclinical, R&D stage. These reasons include the need to express antibodies from primary B cells, a surface display library, convert chimeric antibodies to fully human antibodies, humanization of rodent antibodies, and isotype switching. We have developed a recombinant expression system for drug discovery with the ability to express a large number of recombinant antibodies in a timely, cost-efficient manner.