Antibody–drug conjugates as novel anti-cancer chemotherapeutics

Abstract

SynopsisOver the past couple of decades, antibody-drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics.

Preclinical Antitumor Efficacy of BAY 1129980—a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody–Drug Conjugate for the Treatment of Non–Small Cell Lung Cancer

“…Multiple ADCs targeting various antigens in several cancer types are currently under evaluation in preclinical and clinical studies (39) and auristatin-based conjugates are utilized in approximately half of the ongoing clinical studies with ADCs (32). However, to our knowledge, there are only a few other ADCs in development for the treatment of NSCLC and none of them target C4.4A, making our approach unique.…”

Entwicklung Pyrrolobenzodiazepin(PBD)‐haltiger Antikörper‐Wirkstoff‐Konjugate (ADCs) ausgehend von Anthramycin

“…[92] Der auf CD20 [94] aber mittlerweile zurückgezogen wurde. [95] Derzeit sind zwei ADCs für die Krebstherapie zugelassen, und mehr als 55 andere befinden sich momentan in frühen oder späten Stadien der klinischen Entwicklung. [91] [98] und SGN-CD70A [99] (Abbildung 15), die derzeit in klinischen Studien der Phase III bzw.…”

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

“…Antibodies (their size is about 12 nm) endowed with fluorescent dyes (e.g., Alexa Fluor 488 λEm=525 nm and Texas Red λEm=609 nm) [15][16][17] were used in the development of a wide range of effective targeted therapies [18][19][20][21][22] but they create clustering artifacts due to limited antibody penetration, which have an impact on insufficient labeling density. Thus, ligands that have been exploited for chemotherapeutic agent targeting systems can include monoclonal antibodies [23][24][25][26][27][28] but also low molecular weight receptor-binding conjugates such as dyelabeled peptides (arginine-glycine-aspartic acid-Cyt5,5) [29], peptide hormones [30,31], receptor antagonist and agonists [32], aptamers [33][34][35], transferrin [36][37], oligosaccharides [38], glycoconiugates [39], polyunsaturated fatty acids [40], oligopeptides [41,42], vitamin B12 [43], folic acid [44][45][46][47][48][49][50][51][52][53][54] and hyaluronic acid [55,56]. These ligands can be regarded as a tumor-specific receptor to construct a "guided molecular ...…”