Development of optimal Lu-177 labeled monoclonal antibody (7E11) constructs for radioimmunotherapy of prostate cancer

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4765 Background: Prostate-specific membrane antigen (PSMA) is highly over expressed on the surface of prostate cancer cells. Radioimmunoimaging using an anti-PSMA monoclonal antibody (7E11) coupled to Indium-111 via the bifunctional chelating agent (BFC) GYK-DTPA is currently FDA approved. In prior clinical studies evaluating therapeutic constructs of this antibody and BFC labeled with Y-90, the dose that could be safely administered was limited by toxicity secondary to loss of radionuclide from the BFC. We have investigated the use of kinetically inert cyclic BFCs (of the DOTA family) conjugated to this antibody and labeled with Lutetium-177 to produce immunoconjugates that reduce radiation doses to bone marrow thereby allowing administration of higher and potentially more efficacious doses. Methods: A number of DOTA based 7E11 immunoconjugates were generated using a variety of pH, ionic and temperature conditions. Characterization of the resultant immunoconjugates was performed using SDS-PAGE and HPSEC to assess purity and apparent molecular weight and MALDI-MS to determine ratios of BFC to antibody. Specificity and biological activity of the resultant conjugates were evaluated using an immunoaffinity binding ELISA that targets the N-terminal epitope on PSMA recognized by 7E11. Optimal radiolabeling conditions using Lu-177 have also been determined. Results: Conjugation of DOTA based BFC to 7E11 has been achieved using conditions that preserve the integrity of 7E11 and its ability to specifically bind PSMA. Molar ratios of linker to antibody ranged from 0.2 to 5.3. Purity of the immunoconjugates ranged from 96% to 98%. These conjugates have also been shown to be more stable than previous constructs resulting in lower levels of loss of radionuclide in both in vitro and in vivo studies. Conclusions: Based on these studies, a Lutetium-177 labeled radioimmunoconjugate that should allow administration of higher doses than previous constructs has been developed and is being scaled up for human clinical testing. No significant financial relationships to disclose.