Antibody-Drug Conjugates: Functional Principles and Applications in Oncology and Beyond

Abstract

In the era of precision medicine, antibody-based therapeutics are rapidly enriched with emerging advances and new proof-of-concept formats. In this context, antibody-drug conjugates (ADCs) have evolved to merge the high selectivity and specificity of monoclonal antibodies (mAbs) with the cytotoxic potency of attached payloads. So far, ten ADCs have been approved by FDA for oncological indications and many others are currently being tested in clinical and preclinical level. This paper summarizes the essential components of ADCs, from their functional principles and structure up to their limitations and resistance mechanisms, focusing on all latest bioengineering breakthroughs such as bispecific mAbs, dual-drug platforms as well as novel linkers and conjugation chemistries. In continuation of our recent review on anticancer implication of ADC’s technology, further insights regarding their potential usage outside of the oncological spectrum are also presented. Better understanding of immunoconjugates could maximize their efficacy and optimize their safety, extending their use in everyday clinical practice.

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

“…In recent years, antibody–drug conjugates (ADCs) have emerged as a precise and powerful tool in cancer treatment [ 266 ]. These bioconjugates consist of an mAb that specifically binds a tumor surface antigen and a potent drug, such as monomethylauristatin E, calicheamicin, maytansinoid, or camptothecin [ 267 ].…”

Trends and Perspectives of Biological Drug Approvals by the FDA: A Review from 2015 to 2021

“…Daratumumab Darzalex TM is also undergoing evaluation for other types of cancer, including refractory or relapsed non-Hodgkin’s Lymphoma [ 27 ]. mAbs can also be conjugated to toxins or drugs without compromising healthy tissues around the target fragment or at least minimizing effects in other tissues [ 134 ]. Apart from mAbs, we found that potential to be further evaluated for other therapeutic indications also in the antibody namely Efgartigimod Vyvgart TM in the future [ 80 ].…”

A homogeneous high-DAR antibody–drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides

“…Antibody-drug conjugates (ADCs) have become mainstays as celltargeted delivery vehicles for small molecules and are poised to have broad impact as therapeutics for a range of human diseases. 1,2 The rst generation of ADCs directed potent, broadspectrum cytotoxic agents to tumor cells; aer decades of research several such ADCs have gained approval for clinical use against various cancers. 1,3 The scope of payloads benetting from antibody-mediated delivery (AMD) to human cells has in recent years been expanding and now includes steroids, 4,5 TLR agonists, 6 oligonucleotides, 7 bifunctional degraders, 8 epigenetic modulators 9 and other molecules.…”

“…Since early ADC studies demonstrated such deleterious effects at DAR ¼ 8, 14 a longstanding practical limit has existed: the vast majority of reported ADCs, including most clinically-approved agents, have DAR < 4 (Scheme 1A). 2,3 Motivation to deliver novel payloads via AMD has inspired efforts to increase payload loading although few have led to ADCs with DAR > 4 that are also effective in vivo. The most precedented approach involves incorporation of PEG or another hydrophilic moiety between antibody and payload, which has led to effective ADCs wherein all 8 interchain Cys residues are conjugated (i.e., DAR ¼ 8; Scheme 1B).…”

“… 1,3 The scope of payloads benefitting from antibody-mediated delivery (AMD) to human cells has in recent years been expanding and now includes steroids, 4,5 TLR agonists, 6 oligonucleotides, 7 bifunctional degraders, 8 epigenetic modulators 9 and other molecules. 2 We recently described antibody–antibiotic conjugates (AACs) for the treatment of Staphylococcus aureus infections, exemplifying successful AMD to bacteria. 10 Despite these advances, there continue to exist biological limits to AMD effectiveness, including receptor expression level, internalization rate, tissue penetration and circulation half-life.…”