AN ANTIBODY-REACTIVE WITH DOMAIN-4 OF THE PLATELET-DERIVED GROWTH-FACTOR-BETA RECEPTOR ALLOWS BB BINDING WHILE INHIBITING PROLIFERATION BY IMPAIRING RECEPTOR DIMERIZATION

A panel of murine monoclonal antibodies was generated against the extr acellular domain of the human platelet-derived growth factor (PDGF) be ta receptor (PDGFR beta). These antibodies were assayed for both the a bility to inhibit binding of PDGF BB 60 PDGFR beta(+) cells as well as the capacity to inhibit PDGF BB-mediated mitogenesis, As expected, al l antibodies that could pre vent PDGF BB binding also inhibited mitoge nesis. However one antibody (M4TS.11), with no detectable ability to i nhibit PDGF BE binding, was a potent inhibitor of proliferation induce d by PDGF EB. Further characterization indicated that M4TS.11 impaired PDGFR beta dimerization, revealing the mechanism by which it prevente d PDGF EB-mediated mitogenesis, Using domain deletion mutants of the e xtracellular portion of PDGFR beta, the determinant recognized by this antibody was localized to the fourth extracellular domain of PDGFR be ta, indicating that this domain, which is not involved in ligand bindi ng, actively participates in receptor dimerization and signal transduc tion. The M4TS.11 antibody could also inhibit PDGF BB-mediated prolife ration of responsive cells from both the baboon and the rabbit, indica ting the determinant recognized by the antibody is not limited to huma ns and making it possible to use this antibody to evaluate the therape utic benefit of interfering with PDGF in animal models of human diseas e.