A prostate-specific membrane antigen-targeted monoclonal antibody-chemotherapeutic conjugate designed for the treatment of prostate cancer.
MLN2704 is an antibody-chemotherapeutic conjugate designed to target prostate-specific membrane antigen (PSMA). PSMA is a transmembrane receptor whose expression is largely restricted to prostatic epithelium and prostate cancer cells with its expression level increasing during the progression of malignancy. MLN2704 consists of a de-immunized, monoclonal antibody that is specific for PSMA conjugated to drug maytansinoid 1 (DM1), a microtubule-depolymerizing compound. After antibody binding to PSMA and the subsequent cellular internalization of this complex, DM1 is released leading to cell death. MLN2704 has an approximate half-life of 39 hours in scid mice bearing CWR22 tumor tissue, and the antibody effectively penetrates xenograft tumor tissue. Optimization of dosage and schedule of MLN2704 administration defined interdependency between these conditions that maximized efficacy with no apparent toxicity. Tumor growth delays of approximately 100 days could be achieved on the optimized schedule of one dose of 60 mg/kg MLN2704 every 14 days for five doses (q14dx5). The unconjugated antibody (MLN591) demonstrated essentially no antitumor activity and DM1 alone or a non-PSMA targeted antibody-DM1 conjugate was only weakly active. Furthermore, we show that MLN2704 is active in a novel model of osteoblastic prostate cancer metastasis.
Henry
Michael D
MD
Department of Cancer Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Wen
Shenghua
S
Silva
Matthew D
MD
Chandra
Sudeep
S
Milton
Mark
M
Worland
Peter J
PJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000954:Antigens, Surface; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000556:secondary; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008297:Male; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000628:therapy*; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D000922:Immunotoxins; D008453:Maytansine; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II