Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients

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.

A Purification Strategy Utilizing Hydrophobic Interaction Chromatography to Obtain Homogeneous Species from a Site-Specific Antibody Drug Conjugate Produced by AJICAP™ First Generation

“…Recent years have seen rapid growth in the research and development of antibody drug conjugates (ADCs), with 7 ADCs approved for clinical use by the Food and Drug Administration (FDA) and over 85 ADCs currently in clinical development [1][2][3]. All of the current ADCs on the market have a stochastic distribution of cytotoxic drugs conjugated to multiple sites of the antibody, leading to variation between batches in both the drug to antibody ratio (DAR) and the drug-linker attachment sites [4].…”

Disentangling the therapeutic tactics in GBM: From bench to bedside and beyond

“…ADCs have been exemplified in targeting tumor‐selective antigens and have also provided a better understanding of the BBB (Lucas et al, 2019). It can be employed as a monotherapy or in combination with other therapeutic approaches to improve GBM patient outcomes (Chandramohan et al, 2019).…”

ErbB2 Targeted Epigenetic Modulation: Anti-tumor Efficacy of the ADC Trastuzumab-HDACi ST8176AA1

“…Tumor volume was calculated by using the following formula: V = Length × Width2/2. All experimental animals were euthanized when the tumors reached a volume ≥ 1,200 mm 3 , as required by institutional guidelines.…”

“…Biotechnology R&D, Alfasigma SpA, Rome, Italy,2 Dipartimento di Biotecnologia, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy,3 Lead Discovery Siena srl, Siena, Italy,4 Fondazione Toscana Life Sciences, Siena, Italy,5 Histo-Cyto Service srl, Rome, Italy…”