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Antibody–Drug Conjugates Published OnlineFirst April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Review Clinical Cancer Research Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index Steven Coats1, Marna Williams1, Benjamin Kebble1, Rakesh Dixit1, Leo Tseng1, Nai-Shun Yao1, David A. Tice1, and Jean-Charles Soria1,2 Abstract Since the first approval of gemtuzumab ozogamicin nism of activity of the cytotoxic warhead. However, the (Mylotarg; Pfizer; CD33 targeted), two additional antibody– enthusiasm to develop ADCs has not been dampened; drug conjugates (ADC), brentuximab vedotin (Adcetris; Seat- approximately 80 ADCs are in clinical development in tle Genetics, Inc.; CD30 targeted) and inotuzumab ozogami- nearly 600 clinical trials, and 2 to 3 novel ADCs are likely cin (Besponsa; Pfizer; CD22 targeted), have been approved for to be approved within the next few years. While the hematologic cancers and 1 ADC, trastuzumab emtansine promise of a more targeted chemotherapy with less tox- (Kadcyla; Genentech; HER2 targeted), has been approved to icity has not yet been realized with ADCs, improvements treat breast cancer. Despite a clear clinical benefit being dem- in technology combined with a wealth of clinical data are onstrated for all 4 approved ADCs, the toxicity profiles are helping to shape the future development of ADCs. In this comparable with those of standard-of-care chemotherapeu- review, we discuss the clinical and translational strategies tics, with dose-limiting toxicities associated with the mecha- associated with improving the therapeutic index for ADCs. Introduction in antibody, linker, and warhead technologies in significant depth (2, 3, 8, 9). Antibody–drug conjugates (ADC) were initially designed to leverage the exquisite specificity of antibodies to deliver targeted potent chemotherapeutic agents with the intention of improving Overview of ADCs in Clinical Development the therapeutic index (the ratio between the toxic dose and the Four ADCs have been approved over the last 20 years (Fig. 2A; dose at which the drug becomes effective; Fig. 1; refs. 1, 2). ref. 2). The first ADC approved for clinical use was gemtuzumab Unfortunately, the greatest challenge to date for developing ADCs ozogamicin (Mylotarg; Pfizer; CD33 targeted) for relapsed acute is a therapeutic index far narrower than expected (3–5). Of myeloid leukemia in 2000 (10). In 2010, gemtuzumab ozoga- approximately 55 traditional ADCs for which clinical develop- micin was withdrawn from the U.S. market when a confirmatory ment has been halted, we estimate that at least 23 have been trial showed that it was associated with a greater rate of fatal discontinued due to a poor therapeutic index; however, this is toxicities versus standard-of-care chemotherapy (5.8% vs. 0.8%; likely a conservative estimate based on the availability of clinical refs. 10, 11). In 2017, gemtuzumab ozogamicin was reapproved data. A narrow therapeutic window limits the dose that can be for relapsed/refractory acute myeloid leukemia after a phase III achieved, often resulting in toxic effects occurring before an ADC trial with a fractionated dosing schedule lowered the peak serum reaches its maximally efficacious dose. Furthermore, these toxi- concentration and improved the safety profile, with a complete cities limit the number of dosing cycles that patients can tolerate response rate of 26% (12). These clinical data demonstrate the and often result in skipped doses, dose reductions, or study importance of understanding the relationship between the expo- discontinuations (6, 7). sure, safety, and efficacy of ADCs in clinical development. In this review, we discuss clinical and translational strategies to Other ADCs that have been approved are brentuximab vedotin improve the therapeutic index of ADCs that are based on the latest (Adcetris; Seattle Genetics, Inc.; CD30 targeted; ref. 13) and clinical efficacy and safety data with next-generation antibodies inotuzumab ozogamicin (Besponsa; Pfizer; CD22 targeted; and warheads currently in development. While technology plays a ref. 14), which were approved for hematologic malignancies, and crucial role in expanding the therapeutic index of ADCs, we refer trastuzumab emtansine (Kadcyla; Genentech; HER2 targeted), readers to several excellent reviews that cover novel advancements which was approved for breast cancer (15). Across phase II and III studies, response rates were significantly higher in patients treated with ADCs than in those treated with standard intensive 1AstraZeneca, Gaithersburg, Maryland. 2Universite Paris-Sud, Orsay, France. chemotherapy (14, 16–18). Corresponding Author: Steven Coats, Research and Development Oncology, Clear clinical benefits have been demonstrated with all 4 AstraZeneca, 1 MedImmune Way, Gaithersburg, MD 20878. Phone: 301-398- fi 5207; Fax: 301-398-9400; E-mail: [email protected] approved ADCs; however, each has reported toxicity pro les that are specific to its cytotoxic warhead and, therefore, they cannot be Clin Cancer Res 2019 differentiated from standard-of-care chemotherapies (13–15) in doi: 10.1158/1078-0432.CCR-19-0272 terms of safety. Regardless of the obstacles, there is intense interest Ó2019 American Association for Cancer Research. in developing ADCs—approximately 80 ADC candidates are www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Coats et al. Conjugation/linker • Several chemistries • Multiple DARs • Tumor-specific triggers Antibody • Formats: i.e., antibody fragments • Half-life extension • CDR-masking technologies • Enhance drug delivery Payload • Match right payload MOA for right target/patient population • Alternative warheads: i.e., targeted agents in both tumor and tumor microenvironment © 2019 American Association for Cancer Research Figure 1. ADC structure and therapeutic index optimization strategies. ADCs comprised a tumor-specific antibody, a linker, and a cytotoxic payload. Advances in chemistry of all three components are underway to potentially increase the therapeutic index. CDR, complement-determining region; DAR, drug-antibody ratio; MOA, mechanism of action. reportedly in clinical development, with nearly 600 clinical trials 2.4 mg/kg, showed limited efficacy, and was terminated due to ongoing—and it is likely that several new ADCs will be approved high toxicity (23). over the next few years (Fig. 2A; ref. 19) led by the recent Biologics The results from this phase I trial with sacituzumab govitecan License Application filing for polatuzumab vedotin (CD79b provide an example of the importance of matching the right drug targeted) in relapsed/refractory diffuse large B-cell lymphoma. to the right target for the right patient. Even when comparing Although ADCs have not yet delivered on the promise of a more- ADCs that use the same antibody against the same target in a targeted chemotherapy with an improved toxicity profile, new similar patient population, trastuzumab emtansine and trastu- strategies may prove crucial to improving the therapeutic index of zumab deruxtecan have demonstrated clinical activity, whereas a ADCs (4, 20, 21). These strategies include the use of warheads trastuzumab tesirine conjugate (ADCT-502) was recently discon- with lower potencies and alternative mechanisms of activity as tinued due to a narrow therapeutic index (24). HER2 is known to described below. be expressed in several normal tissues such as in the lung and the Two examples of ADCs in clinical development that use war- gastrointestinal tract (25). This creates two potential problems for heads that inhibit topoisomerase I activity include trastuzumab an ADC. First, the normal expression of the antigen creates a sink deruxtecan targeting HER2 in breast and gastric cancers and for the ADC that must be overcome to maximize exposure to the sacituzumab govitecan targeting Trop2 in breast and lung can- tumor (26, 27). Given the high potency of the tesirine payload, cers (22, 23). A Biologics License Application has been filed for doses sufficient to overcome the HER2 normal tissue sink might sacituzumab govitecan for metastatic triple-negative breast can- not be achievable. Second, the normal expression of the antigen cer, and trastuzumab deruxtecan is currently in multiple late-stage can result in on-target toxicity. In the case of trastuzumab tesirine, pivotal clinical trials. The clinical data for trastuzumab deruxtecan pulmonary edema, a known toxicity of pyrrolobenzodiaze- from an ongoing phase I study in HER2-high metastatic breast pines (28), may have been exacerbated by the expression of HER2 cancer (post trastuzumab emtansine) showed an objective in lung tissues. While general characteristics of an ADC target, such response rate (ORR) of 55% with median progression-free sur- as tumor-to-normal expression ratios and internalization kinetics, vival not reached (Table 1). Updated recent data have shown a may be considered, both the HER2 and Trop2 examples provide median duration of response of 20.7 months, which compares evidence that achieving clinical success with an ADC may depend favorably with trastuzumab emtansine, which, in a pivotal study on matching the technology and the target. in HER2-high metastatic breast cancer, showed an ORR of 43.6%, The non–target-mediated uptake of the cytotoxic drug into a median progression-free survival of 9.6 months, and a median normal tissues remains a
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