Journal article
A prostate-specific membrane antigen-targeted monoclonal antibody-chemotherapeutic conjugate designed for the treatment of prostate cancer
Cancer research (Chicago, Ill.), Vol.64(21), pp.7995-8001
2004
DOI: 10.1158/0008-5472.CAN-04-1722
PMID: 15520207
Abstract
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 ∼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.
Details
- Title: Subtitle
- A prostate-specific membrane antigen-targeted monoclonal antibody-chemotherapeutic conjugate designed for the treatment of prostate cancer
- Creators
- Michael D Henry - Millennium Engineering and IntegrationSHENGHUA Wen - Department of Cancer Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United StatesMatthew D Silva - Department of Imaging Sciences, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United StatesSudeep Chandra - Department of Imaging Sciences, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United StatesMark Milton - Department of Drug Safety and Disposition, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United StatesPeter J Worland - Department of Cancer Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.64(21), pp.7995-8001
- Publisher
- American Association for Cancer Research
- DOI
- 10.1158/0008-5472.CAN-04-1722
- PMID
- 15520207
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 2004
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Radiation Oncology
- Record Identifier
- 9984302194402771
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