(formerly Synthon Biopharmaceuticals) developed trastuzumab duocarmazine (SYD985) [104], an ADC with an average DAR of 2

(formerly Synthon Biopharmaceuticals) developed trastuzumab duocarmazine (SYD985) [104], an ADC with an average DAR of 2.8, resulting from the combination of an anti-HER2 mAb and a duocarmycin precursor (seco-DUBA), linked by a cleavable linker sensitive to cathepsin B, optimized by the presence of two small pegylated units to ensure better solubility (and therefore better conjugation) of the linker-payload moieties (Figure 14). combination with conventional chemotherapy or checkpoint inhibitors, and their design for applications beyond oncology, to make ADCs the magic bullet that Paul Ehrlich dreamed of. Keywords: antibodyCdrug conjugate, ADC, bioconjugation, linker, payload, cancer, resistance, combination therapies 1. Introduction/History AntibodyCdrug conjugates Schisandrin A (ADCs) have made considerable progress in 10 years. ADC is a vector-based chemotherapy that allows the selective delivery of a potent cytotoxic agent within a tumor. An ADC results from the generally stochastic grafting of a cytotoxic agent onto a monoclonal antibody (mAb) via a judiciously constructed spacer arm [1,2]. This is a complex mixture of immunoconjugates with different DLD (drug loading and distribution) and DAR (drug-to-antibody ratio, corresponding to the number of cytotoxics grafted onto the mAb) [3]. In 2009 2009 gemtuzumab ozogamicin (Mylotarg?) was the only ADC approved by the Food and Drug Administration (FDA) and 12 other candidates were in clinical studies [4]. At present, 8 other ADCs have been approved and more than 80 others are in active clinical studies, including 6 in phase III or pivotal phase II (Table 1) [5]. More than 50 candidates have also been abandoned in the clinic mainly for toxicological reasons or because of Schisandrin A a lack of efficiency. ADCs targeting solid tumors are currently making a satisfactory breakthrough in Schisandrin A the clinic. Until November 2019, only Kadcyla? had an indication in solid tumors. With the late 2019 FDA-approval of both Padcev? and Enhertu?, and Trodelvy? in April 2020, there are currently four FDA-approved ADCs directed against solid tumors. The other five ADCs are indicated in hematological cancers and are generally considered to be easier to target with ADCs. In addition, ADCs in the advanced clinical phase are mainly directed against solid tumors (four against solid Schisandrin A tumors; two directed against lymphomas). Table 1 AntibodyCdrug conjugates (ADCs) approved by the Food and Drug Administration (FDA), in advanced clinical trials (Phase III or pivotal phase II) or recently stopped. more than forty years ago. HDP-101 (Figure 11) is the most advanced ATAC. HDP-101 results from the site-specific conjugation of HDP 30.2115, a stabilized analog of -amanitin, onto a Schisandrin A Thiomab (designed by Genentech) targeting the B-cell maturation antigen (BCMA, CD269) through a cathepsin B-sensitive linker, to produce an NEK3 ATAC with a DAR of 2. BCMA has emerged as a very selective target of choice for the treatment of multiple myeloma [95]. In vitro, HDP-101 was tested on various multiple myeloma cells taken from patients, including non-dividing cells or cells with a low concentration of BCMA antigens (down to 270 copies per cell) [96]. In all cases, the observed IC50 of the ATAC HDP-101 was in the picomolar range. Due to the hydrophilicity of the amatoxins, the observed IC50 of the ATAC HDP-101 is 20,000-fold higher (around 100 pM) than the IC50 of its free amatoxin HDP 30.2115. No toxicity was observed on non-BCMA expressing cells. Therefore, the ATAC mechanism is only based on the internalization of the ATAC-Ag complex followed by its lysosomal degradation in BCMA-positive tumor cells. In vivo, in various xenograft models of multiple myeloma, HDP-101 led to complete tumor remission in mice, and safety studies identified a very favorable therapeutic window in mice and monkeys. ATACs are a very promising class of compounds, still in a preclinical phase, although their chemistry manufacturing control (CMC) process has been successfully carried out. Open in a separate window Figure 11 HDP-101 formula, ADC with a DAR 2, resulting from the site-specific conjugation of an -amanitin analog (HDP 30.2115) onto an anti-BCMA Thiomab via a cathepsine B-sensitive linker. 5.6. Combined Strategies beyond Dogmas: Pivotal Phase II or Phase III ADC The development of first and especially second-generation ADCs has been associated with many dogmas, which many studies have considered as rules to follow in order to develop ADCs with better chances of success. Among these dogmas, we can cite targeting of an Ag not expressed in a ubiquitous manner, with a high overexpression level and internalizing, in particular to allow the intracellular.