Antibody Conjugates-Recent Advances and Future Innovations

Abstract

Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Clinical success rates of antibodies have exceeded expectations, resulting in heavy investment in biologics discovery and development in addition to traditional small molecules across the industry. However, protein therapeutics cannot drug targets intracellularly and are limited to soluble and cell-surface antigens. Tremendous strides have been made in antibody discovery, protein engineering, formulation, and delivery devices. These advances continue to push the boundaries of biologics to enable antibody conjugates to take advantage of the target specificity and long half-life from an antibody, while delivering highly potent small molecule drugs. While the “magic bullet” concept produced the first wave of antibody conjugates, these entities were met with limited clinical success. This review summarizes the advances and challenges in the field to date with emphasis on antibody conjugation, linker-payload chemistry, novel payload classes, absorption, distribution, metabolism, and excretion (ADME), and product developability. We discuss lessons learned in the development of oncology antibody conjugates and look towards future innovations enabling other therapeutic indications.

How to select IgG subclasses in developing anti-tumor therapeutic antibodies

“…Although the primary efficacy of ADC drugs is mediated by the toxic payloads delivered by antibodies, the Fc-mediated effector functions may also contribute to the therapy, which is impacted by the expression and cellular distribution of the targets. Among the currently approved five ADC drugs [74] (Table 6), two employed IgG4 antibodies which are lack of effector functions, while all other three employed IgG1, of which brentuximab vedotin has been reported to induce ADCP in vivo and contribute to the potent anti-tumor efficacy for this ADC [75,76]. However, other studies have identified Fc receptor engagement by ADC may cause side effects.…”

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

“…Unpurified trastuzumab-AJICAP™-MMAE (4) was synthesized according to our previous procedure [20]. Peptide reagent (1) was reacted with trastuzumab to produce the trastuzumab-peptide conjugate (2). Treatment of 2 by Tris (2-carboxyethyl)phosphine (TCEP) clipped off peptide moiety from 2 involving cleavage of interchain disulfide bonds.…”

“…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].…”

Insight into Temperature Dependency and Design of Experiments towards Process Development for Cysteine‐Based Antibody‐Drug Conjugates

“…In the last ten years, antibody-drug conjugates (ADCs) have become a promising approach for oncological therapeutics. [1][2][3] To date, seven ADCs are on the commercial market: Adcetris (brentuximab vedotin) from Seattle Genetics and Takeda, Kadcyla (trastuzumab emtansine) and Polivy (polatuzumab vedotin) from Genentech, Mylotarg (gemtuzumab ozogamicin) and Besponsa (inotuzumab ozogamicin) from Pfizer, Padcev (enfortumab vedotin) from Astellas and Seattle Genetics, and Enhertu (trastuzumab deruxtecan) from Daiichi-Sankyo and AstraZeneca. In 2019, three ADCs (Polivy, Pedcev and Enhertu) were approved by the Food and Drug Administration (FDA), and currently there are more than 85 ADCs in clinical trials [2,3] .…”