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Summary of a workshop on preclinical and translational safety assessment of CD3 bispecifics
Cris Kamperschroer1, Jacintha Shenton2, Hervé Lebrec3
1Pfizer Worldwide Research and Development, Groton, CT, USA.
Abstract:
Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity. Another key challenge is to arrive at a safe clinical starting dose and an efficient escalating strategy that allows patients in early dose cohorts the potential for clinical benefit in Phase 1 trials. To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges through improvements in molecular design, preclinical safety assessment strategies, and clinical management practices. A recent workshop at the U.S. Food and Drug Administration (FDA) with industry, academic, and regulatory agency representation was held to discuss the challenges and explore where such improvements to the development of CD3 bispecifics can be implemented. Here, the content of the presentations and the discussion that occurred during this workshop are summarized.
Insights
Developing novel CD3 bispecifics for cancer therapy faces challenges like cytokine release syndrome and off-tumor toxicity. This summary highlights a workshop focused on improving molecular design and clinical strategies for safer, more effective treatments.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Numerous CD3 bispecific antibodies are in development for treating various cancers.
- Key safety concerns include cytokine release syndrome (CRS), off-tumor toxicity, and neurotoxicity.
- Establishing safe clinical starting doses and escalation strategies is crucial for early-phase trials.
Purpose of the Study:
- To summarize discussions from an FDA workshop on challenges in CD3 bispecific antibody development.
- To explore potential improvements in molecular design, preclinical assessment, and clinical management.
- To enhance the therapeutic index and expand treatment options for cancer patients.
Main Methods:
- Summary of presentations and discussions from a workshop involving industry, academia, and regulatory agencies.
- Review of current preclinical and clinical development strategies for CD3 bispecifics.
- Analysis of safety concerns and proposed solutions.
Main Results:
- Identified excessive cytokine release, off-tumor/on-target cytotoxicity, and neurotoxicity as primary safety concerns.
- Highlighted the challenge of determining safe clinical starting doses and effective dose escalation.
- Emphasized the need for improved molecular designs and preclinical safety assessments.
Conclusions:
- Intense efforts are underway to overcome safety challenges through improved molecular design and clinical strategies.
- Collaborative discussions aim to refine development pathways for CD3 bispecifics.
- The goal is to bring safer and more effective bispecific antibody therapies to patients.
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