Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

Abstract

With more than 90 approved drugs by 2020, therapeutic antibodies have played a central role in shifting the treatment landscape of many diseases, including autoimmune disorders and cancers. While showing many therapeutic advantages such as long half-life and highly selective actions, therapeutic antibodies still face many outstanding issues associated with their pharmacokinetics (PK) and pharmacodynamics (PD), including high variabilities, low tissue distributions, poorly-defined PK/PD characteristics for novel antibody formats, and high rates of treatment resistance. We have witnessed many successful cases applying PK/PD modeling to answer critical questions in therapeutic antibodies’ development and regulations. These models have yielded substantial insights into antibody PK/PD properties. This review summarized the progress, challenges, and future directions in modeling antibody PK/PD and highlighted the potential of applying mechanistic models addressing the development questions.

Impact of charge patches on tumor disposition and biodistribution of therapeutic antibodies

“…Many therapeutic antibodies, in particular those directed against solid tumors, will need to reach the tissue interstitium to elicit their therapeutic effect (Tang and Cao 2021;Khaowroongrueng et al 2021). Interstitial concentrations were first derived assuming a constant interstitial volume fraction.…”

“…Arguably, it is the delivery to the target site, which restricts efficacy of antibody therapy in many cases. In particular, improving uptake into solid tumors is an important challenge for current research (Tang and Cao 2021). The presence of cells exposed to insufficient amounts of antibody within a tumor under treatment not only restricts efficacy, but may also foster the development of resistance against a targeted treatment (Thurber et al 2008).…”

“…1a (Dostalek et al 2013;Thurber et al 2008;Shah and Betts 2012)). The site of action for most antibody therapeutics of solid tumors is the cellular surface, accessed from the interstitial space (Tang and Cao 2021). Several barriers need to be crossed to reach this compartment and distribute homogeneously (Fig.…”

Single-Dose P2 X4R Single-Chain Fragment Variable Antibody Permanently Reverses Chronic Pain in Male Mice

“…Due to their solubility and small size, which allows them to cross the blood-nerve and blood-brain barriers, scFvs are being investigated as therapeutics for arthritis, Alzheimer's, Parkinson's, Creutzfeldt-Jacob, and Huntington's disease [43][44][45]. Computational modeling allows predictive illustration of the binding to target proteins [46]. The scFvs can be easily modified with an in vivo half-life for short-term diagnostic or long-term biotherapeutic applications for both the nervous and immune systems.…”

Physiological Considerations for Modeling in vivo Antibody-Target Interactions

“…With a phase I to approval success rate of approximately 22% ( Kaplon and Reichert, 2019 ), nearly double that of small molecule drugs, drug developers are increasingly shifting their focus toward protein drug development ( Kaplon et al, 2020 ). Although antibodies and small molecule drugs share similar clinical development paths, antibody-based therapeutics present unique challenges from the early stage of candidate selection to the late stage of therapeutic confirmation ( Tang and Cao, 2021 ).…”