It will be interesting to see comparison with MLN2704.
B210 Fully human anti-PSMA monoclonal antibodies for prostate cancer therapy.
Dangshe Ma, Jason P. Gardner, Christine Hopf, Michael Cohen, Gerald P. Donovan, Norbert Sch¨¹lke, Warren D. W. Heston, and William C. Olson. The PSMA Development Company LLC (Joint Venture between Progenics Pharmaceuticals Inc. and Cytogen Corp.), Tarrytown, NY and Cleveland Clinic Foundation, Cleveland, OH.
Prostate cancer is the most commonly diagnosed nondermatological malignancy in men and accounts for 30,000 deaths annually in the United States. The primary organ-confined cases can effectively be treated and cured by surgery and/or radiation therapy. Relapsed or more advanced disease is treated with androgen depletion. Unfortunately, almost all tumors become hormone-resistant and progress rapidly in the absence of any effective therapy. There is an urgent need for novel, molecularly targeted immunotherapeutics for treatment of recurrent prostate cancer. Prostate-specific membrane antigen is widely regarded as a compelling target for immunotherapy of prostate cancer. Due to the differential expression of mRNA splice variants, PSMA is found in normal prostate as a cytoplasmic protein and in prostate cancer as a homodimeric type II membrane glycoprotein whose surface expression increases with disease progression. PSMA is both rapidly internalized upon antibody binding and enzymatically active. Collectively, the expression profile and biological properties of PSMA make this molecule a highly attractive target for prostate cancer therapy. Using novel recombinant forms of PSMA and XenoMouse technology (abgenix, Fremont, CA), we generated a panel of fully human IgG1 monoclonal antibodies (mAbs) against PSMA, and these mAbs specifically recognize conformational epitopes on PSMA with sub-nanomolar affinity. Our panel includes novel human mAbs that specifically recognize homodimeric but not monomeric forms of PSMA (Sch¨¹lke et al., PNAS, in press). Here we describe the mAbs¡¯ intrinsic cytotoxic effects as well as their ability to specifically deliver cytotoxic agents to PSMA-expressing tumor cells in vitro and in vivo. Naked mAbs reproducibly induced antibody-dependent cell-mediated cytotoxicity (ADCC) of human prostate cancer cells at nanomolar concentrations in vitro. Toxin-conjugated mAbs rapidly internalized and killed PSMA-expression tumor cells with picomolar potency and >1000-fold selectivity. In a mouse xenograft model, mAbs labeled with a therapeutic beta-emitting isotope, 177Lu, selectively targeted PSMA-expressing solid tumors, with a tumor uptake of 30% injected dose per gram of tumor. A single dose of 400 ¦ÌCi 177Lu-labeled antibody increased median survival times in the animals by 3.5 fold compared to untreated control animals (P<0.05). Based on these studies, a lead fully human antibody has been selected for human clinical testing in naked, radiolabeled and toxin-conjugated forms.
B208 MLN2704 effectively inhibits tumor growth in models of human prostate cancer expressing PSMA.
Shenghua Wen, Matthew Silva, William Riordan, Judy Shi, Elizabeth Young, Molly Meyers, Marie Green, Mark Milton, Sudeep Chandra, Peter J. Worland, and Michael D. Henry. Millennium Pharmaceuticals, Inc., Cambridge, MA.
MLN2704 is a novel therapeutic designed to deliver the maytansinoid chemotherapeutic agent DM1 directly to prostate cancer cells through the MLN591, a targeting monoclonal antibody vehicle (T-MAV), that binds specifically to the prostate-specific membrane antigen (PSMA). Here we report our extended preclinical efficacy study of MLN2704 in PSMA-expressing prostate cancer models. Utilizing the CWR22 subcutaneous prostate cancer xenograft model in scid mice, we describe the serum pharmacokinetics of MLN2704 and show that on an optimized schedule of administration of once every two weeks, MLN2704 treatment delivers dose-dependent antitumor efficacy. At 60mg/kg MLN2704, the highest dose tested, most tumors (5/7) regressed to undetectable levels after completion of the dosing regimen. Although these eventually grew back, there was a significant delay in tumor growth. At this high dose level, there was no evidence of overt toxicity of MLN2704 as animals did not exhibit declines in body weight. We have also examined MLN2704 efficacy in a model of osteoblastic prostate cancer metastasis based on the 22Rv1 prostate cancer cell line, which is an androgen-independent derivative of the CWR22 prostate cancer xenograft. We first engineered PSMA-positive 22Rv1 cells to express firefly luciferase. Clones were selected and evaluated for PSMA and luciferase expression as well as sensitivity to MLN2704. In vitro analysis indicated that sensitivity to MLN2704 was correlated with PSMA expression levels. One luciferase-expressing clone 22Rv1-luc1.17 was selected for analysis in vivo. 1.5X105 22Rv1-luc1.17 cells were injected into the right tibiae of scid mice. Radiographic and histologic analysis revealed that intraosseus 22Rv1-luc1.17 tumors developed osteoblastic or mixed osteoblastic/osteolytic pathology within 10 weeks. We performed in vivo bioluminescent imaging (Xenogen, IVIS) to monitor tumor growth and demonstrated that MLN2704 significantly delayed intraosseous tumor growth and osteoblastic pathologic lesion progression compared to DM1 alone and a non-specific antibody conjugate. We also performed post-mortem high resolution magnetic resonance imaging and confirmed that tumor volume was significantly reduced in MLN2704-treated mice. Additionally, ex vivo micro-CT imaging clearly demonstrated that MLN2704 treatment inhibited the development of osteoblastic lesions in this model. These results suggest that MLN2704 may have activity against osseous metastases in prostate cancer patients. |
