Clinical optimization of pretargeted radioimmunotherapy with antibody-streptavidin conjugate and Y-90-DOTA-biotin

Pretargeted radioimmunotherapy (PRIT) was evaluated using an antibody-strep tavidin conjugate, followed by a biotin-galactose-human serum albumin clear ing agent and Y-90-dodecane tetraacetic acid (DOTA)-biotin as the final ste p for therapy. The objective was to develop a clinical protocol that could show an improved tumor-to-red marrow therapeutic ratio compared with conven tional radioimmunotherapy (RIT) and at the same time preserve the efficienc y of tumor targeting. Method: Forty-three patients with adenocarcinomas rea ctive to NR-LU-10 murine monoclonal antibody received the 3 components. Dos es and timing parameters were varied to develop an optimized schema. In som e patients, the conjugate was radiolabeled with Re-186 as an imaging tracer to assess biodistribution of the conjugate and effectiveness of the cleari ng agent. In-111-DOTA-biotin was coinjected with Y-90-DOTA-biotin for quant itative imaging. Safety, biodistribution, pharmacokinetics, dosimetry, and antiglobulin formation were evaluated. Results: The optimal scheme was defi ned as a conjugate dose of 125 mu g/mL plasma volume followed at 48 h by a clearing agent in a 10:1 molar ratio of clearing agent to serum conjugate. The therapeutic third step was 0.5 mg radiobiotin administered 24 h later. No significant adverse events were observed after administration of any of the components. The mean tumor-to-marrow absorbed dose ratio when using the optimized PRIT schema was 63:1, compared with a 6:1 ratio reported previou sly for conventional RIT. Antiglobulin to murine antibody and to streptavid in developed in most patients. Conclusion: This initial study confirmed tha t the PRIT approach is safe and feasible and achieved a higher therapeutic ratio than that achieved with conventional RIT using the same antibody.