Abstract
The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small molecule drugs, though their clinical use still requires optimization. The pharmacology of mAbs/ADCs is complex and because ADCs are comprised of multiple components, individual agent characteristics and patient variables can affect their disposition. To further improve the clinical use and rational development of these agents, it is imperative to comprehend the complex mechanisms employed by antibody-based agents in traversing numerous biological barriers and how agent/patient factors affect tumor delivery, toxicities, efficacy, and ultimately, biodistribution. This review provides an updated summary of factors known to affect the disposition of mAbs/ADCs in development and in clinical use, as well as how these factors should be considered in the selection and design of preclinical studies of ADC agents in development.
Highlights
The treatment of cancer and other conditions has observed significant progress and growth in treatment choices, with the exponential growth of carrier-based drug systems available
A study by Breij et al revealed that murine patient-derived xenografts of solid tumors administered an antibody-drug conjugates (ADCs) conjugated with monomethyl auristatin E (MMAE) experienced a complete response, despite the ADC target antigen only being expressed on 25–50% of cancer cells [15]
Variability with traditional covariates or anti-drug antibody (ADA) titers was not found in these studies, the high inter-patient variability of ADCs may be related, with similar variability seen in mononuclear phagocyte system (MPS) function
Summary
The treatment of cancer and other conditions has observed significant progress and growth in treatment choices, with the exponential growth of carrier-based drug systems available. If we take into account non-conjugated mAbs, there have been >60 agents approved since the turn of the century (Table 2) Even though these agents have been in clinical use for nearly twenty-five years, the factors affecting the disposition of these antibody-based agents are still being discovered and evaluated. Major challenges remain in how to evaluate the safety and toxicity of these agents using preclinical and clinical models, as well as the variation observed within preclinical models. This high inter-patient variability is clinically important as ADCs have a narrow therapeutic index [1]. We provide additional insight into differences in preclinical models and how variations among models can affect their translation into human clinical trials
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