PT-011 - COMPUTATIONAL SYSTEMS PHARMACOLOGY OF ANTIBODY-DRUG CONJUGATES.

I. Lam¹, V. Pilla Reddy², K. Ball², R. Arends^3,4, D. Dai³, F. Mac Gabhann¹; ¹Johns Hopkins University, Baltimore, MD, USA, ²AstraZeneca, Cambridge, United Kingdom, ³AstraZeneca, Gaithersburg, MD, USA, ⁴Exelixis, Alameda, CA, USA.

Background: Antibody-Drug Conjugates (ADCs) are immunoconjugate drugs with a monoclonal antibody (Ab) attached to cytotoxic small molecules (warheads) via chemical linkers. The Ab targets a tumor antigen, so the warhead can kill tumor cells while sparing healthy tissue. Despite hundreds of clinical trials, only 12 ADCs have been approved for use in oncology. Quantitative systems pharmacology (QSP) models build on traditional PK-PD models to integrate known mechanisms with data at multiple scales, which can strengthen our understanding of ADCs and support the development of improved cancer treatments.

Methods: Using ordinary differential equations, we have constructed a computational model with detailed cellular and intracellular mechanisms specific to ADCs with pyrrolobenzodiazepine (PBD) warheads to simulate the impact of ADC design on in vitro efficacy and toxicity. Parameters were estimated from literature, or calibrated and validated using experimental data for anti-BCMA and anti-HER2-PBD ADCs.

Results: We simulated various ADC design scenarios and examined effects specific to each type of ADC. For the anti-BCMA ADC, simulations showed that adding clinically observed levels of soluble BCMA to the cell culture system does not impact tumor cell killing efficacy, consistent with experimental data. For the anti-HER2 PBD ADC, incorporating known mechanisms such as HER2 homodimerization and phosphorylation resulted in additional internalization and binding of warhead to DNA, leading to increased cell killing.

Conclusion: We have developed an in vitro systems pharmacology model of PBD-ADCs. The model provides mechanistic insight into observed ADC responses and aids in the design of improved therapies, and can be expanded to incorporate whole-body pharmacology to run virtual clinical trials.