Development of a Novel Engineered Antibody Format for PSMA-Targeted Radionuclide Therapy

Prostate cancer remains a prevalent and lethal malignancy across the globe. Despite ongoing advances in therapeutic approaches, these remain ineffective, and new treatments are drastically needed. Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is a well-developed approach for prostate cancer treatment; however, current small molecule and antibody carriers for molecular radiotherapy each have drawbacks in their biodistribution and consequent side effects as highlighted in current clinical trials. To address this, we developed an approach to bioengineer the well clinically validated antibody carrier HuJ591 to yield an engineered, full-length antibody construct that achieves the beneficial fast pharmacokinetic profile of small molecule carriers alongside the enhanced tumor targeting and reduced renal toxicity of antibody carriers. We report here a rational design process to produce a novel humanized PSMA-targeting antibody designed for the delivery of radiation with abrogated FcRn recycling that aims to reduce blood circulation time and minimize systemic exposure. We demonstrate that these IgG-based constructs retain the favorable properties of HuJ591, such as inherent protein stability, expression in systems compatible with industrial manufacture, and comparable, highly specific PSMA-binding characteristics. We then radiolabeled constructs with the diagnostic radionuclide ⁶⁴Cu as a surrogate for therapeutic radionuclide payloads and undertook a proof-of-concept preclinical imaging study to probe the resulting <i>in vivo</i> behaviors. This demonstrated the success of this design strategy to yield the intended <i>in vivo</i> and radiopharmaceutical characteristics, with the resulting construct being rapidly cleared from circulation over 3 days. Together, this study demonstrates the rational design of a novel targeting antibody platform for PSMA-expressing tumors with reduced systemic exposure. Such a platform is extremely promising for future radiotherapeutic delivery approaches, whereby effective tumor treatment can be achieved while mitigating potential hematologic toxicity observed with standard antibody delivery approaches.