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

Pretargeted radioimmunotherapy (PRIT) was evaluated using an antibody-streptavidin conjugate, followed by a biotin-galactose-human serum albumin clearing agent and 90Y-dodecane tetraacetic acid (DOTA)-biotin as the final step for therapy. The objective was to develop a clinical protocol that could show an improved tumor-to-red marrow therapeutic ratio compared with conventional radioimmunotherapy (RIT) and at the same time preserve the efficiency of tumor targeting.

Forty-three patients with adenocarcinomas reactive to NR-LU-10 murine monoclonal antibody received the 3 components. Doses and timing parameters were varied to develop an optimized schema. In some patients, the conjugate was radiolabeled with 186Re as an imaging tracer to assess biodistribution of the conjugate and effectiveness of the clearing agent. 111In-DOTA-biotin was coinjected with 90Y-DOTA-biotin for quantitative imaging. Safety, biodistribution, pharmacokinetics, dosimetry, and antiglobulin formation were evaluated.

The optimal schema was defined as a conjugate dose of 125 microg/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 previously for conventional RIT. Antiglobulin to murine antibody and to streptavidin developed in most patients.

This initial study confirmed that the PRIT approach is safe and feasible and achieved a higher therapeutic ratio than that achieved with conventional RIT using the same antibody.