Mechanistic Quantitative Pharmacology Strategies for the Early Clinical Development of Bispecific Antibodies in Oncology
- Bi-specific antibodies (bsAbs) are crucial in cancer therapy research.
- BsAbs offer advantages such as enhanced efficacy and reduced systemic toxicity.
- Early clinical trials face challenges with dose selection and predicting effective doses.
- Clinical variability is influenced by factors like functional affinity, receptor expression, effector-to-target cell ratio, and soluble targets.
- Mechanistic modeling is essential for navigating complexities in bsAb trials.
- Mechanistic modeling assists in trial design, clinical translation, and reducing dose-limiting toxicities.
- The tutorial demonstrates the impact of mechanistic modeling on decision-making through case studies.
Cancer is a complex, multifactorial disease. Crosstalk between signaling cascades and multiple mediators of tumor survival and immune evasion exist. Genetic alterations lead to heterogeneity in tumor cell antigen expression within and between patients. Acquisition of resistance to therapy is associated with upregulation of alternative receptors as well as pathway switching between receptors. Overall, this means that specific targeting of a single receptor is often insufficient for efficacy and standard of care consists of combinations of therapies to kill tumor cells. However, development of individual drugs for a combination therapy can be a costly and time-consuming process requiring separate manufacturing processes and filing of the safety of each antibody component separately.
During the past decade, advances in protein engineering have resulted in the ability to robustly and cost-effectively synthesize bispecific antibodies (bsAbs) as an alternative to combination therapy or use of mixtures. This has led to an explosion of bsAbs in drug development–currently there are 57 bsAbs in clinical trials in patients with cancer, with a large diversity in formats. Thus far, blinatumomab (Blincyto; Amgen) is the only bsAb approved in oncology. Blinatumomab is a CD19/CD3 bispecific T-cell engager (BiTE), which was initially approved in 2014 for Philadelphia chromosome-negative relapsed or refractory (r/r) B-cell precursor acute lymphoblastic leukemia (ALL) in adults. Since then, it has gained approval for treatment in pediatric patients with ALL and for minimal residual disease-positive B-cell precursor ALL, where it is the first US Food and Drug Administration (FDA) approved treatment for this specific patient population.
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