Abstract
Antibody drug conjugates (ADCs) represent novel anti-cancer modalities engineered to specifically target and kill tumor cells expressing corresponding antigens. Due to their large size and their complex kinetics, these therapeutic agents often face heterogeneous distributions in tumors, leading to large untargeted regions that escape therapy. We present a modeling framework which includes the systemic distribution, vascular permeability, interstitial transport, as well as binding and payload release kinetics of ADC-therapeutic agents in mouse xenografts. We focused, in particular, on receptor dynamics such as endocytic trafficking mechanisms within cancer cells, to simulate their impact on tumor mass shrinkage upon ADC administration. Our model identified undesirable tumor properties that can impair ADC tissue homogeneity, further compromising ADC success, and explored ADC design optimization scenarios to counteract upon such unfavorable intrinsic tumor tissue attributes. We further demonstrated the profound impact of cytotoxic payload release mechanisms and the role of bystander killing effects on tumor shrinkage. This model platform affords a customizable simulation environment which can aid with experimental data interpretation and the design of ADC therapeutic treatments.
Highlights
Antibody-Drug Conjugates (ADCs) are therapeutic hybrid constructs comprised of a potent cancer therapeutic molecule joined by a chemical linker to an antibody directed against a tumor surface antigen
For the first time, we present a mechanism-based PK/PD model that incorporates detailed descriptions of receptor dynamics, payload internalization and release mechanisms, to describe Antibody drug conjugates (ADCs) and payload penetration at the cellular level and within a solid tumor, in order to project the effect in tumor mass fluctuations
Target receptor levels were shown to have an effect on the dynamic fluctuation of tumor mass over time (Fig. 3), as observed from the largely varied responses produced by a single intravenous administration of ADC
Summary
Antibody-Drug Conjugates (ADCs) are therapeutic hybrid constructs comprised of a potent cancer therapeutic molecule joined by a chemical linker to an antibody directed against a tumor surface antigen. The idea of using ADCs for the direct delivery of a cytotoxic agent to the target cells was first described in the 1980s. Recent development and commercialization of two ADCs, trastuzumab DM1 (TDM1) and brentuximab vedotin have demonstrated the practicality of this biotherapeutic modality. TDM1’s clinical success in breast cancer [1, 2] and brentuximab vedotin’s attainment of 35% complete and 40% partial remission in Hodgkin lymphoma [3] have heralded the beginning of a wave of clinical successes. There are currently more than 200 registered clinical trials for ADC reagents, in more than 50 diseases [4].
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