Novel ADCs and Strategies to Overcome Resistance to Anti-HER2 ADCs

Abstract

During recent years, a number of new compounds against HER2 have reached clinics, improving the prognosis and quality of life of HER2-positive breast cancer patients. Nonetheless, resistance to standard-of-care drugs has motivated the development of novel agents, such as new antibody-drug conjugates (ADCs). The latter are a group of drugs that benefit from the potency of cytotoxic agents whose action is specifically guided to the tumor by the target-specific antibody. Two anti-HER2 ADCs have reached the clinic: trastuzumab-emtansine and, more recently, trastuzumab-deruxtecan. In addition, several other HER2-targeted ADCs are in preclinical or clinical development, some of them with promising signs of activity. In the present review, the structure, mechanism of action, and potential resistance to all these ADCs will be described. Specific attention will be given to discussing novel strategies to circumvent resistance to ADCs.

Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs

“…HER2-targeted agents differ in their composition and mechanism of action and can be broadly classified into the following categories: anti-HER2 and pan-HER antibodies (targeting various HER family receptors, such as Sym013), ADCs, antibodies fused to cytotoxic peptides, bispecific antibodies, immunotherapeutic approaches (including peptide vaccines and T-CARs), and TKIs, among others (reviewed in [ 58 ]). The importance of ADCs and HER2-directed immunotherapy agents in current and future treatments have been specifically reviewed [ 14 , 59 ]. In this review, we focus mostly on other approaches.…”

“…Among antibody-derived approaches, ADCs are already a reality and have resulted in encouraging improvement in patient survival; these include T-DM1 (Kadcyla),T-deruxtecan (Enhertu) and Disitamab vedotin (RC48; Aidixi, approved in China for gastric and urothelial carcinoma), which are already used in the clinic, while a large list of other ADCs, including Trastuzumab Duocarmazine (SYD985), ALT-P7, ARX788, A166, BAT8001, and XMT-1522, among others, are under clinical evaluation (revised in [ 14 , 93 ]). Rather than attaching chemotherapeutic or cytotoxic agents to anti-HER2 antibodies (as ADCs do), immunotoxins contain an anti-HER2 antibody or its fragments fused with cell-death-inducing peptides.…”

“…Despite encouraging clinical benefits observed by recent FDA-approved antibody-based approaches and those still under clinical trials, some resistance mechanisms to these new agents have already been reported. Fortunately, some of them could be potentially reversed by targeting other signaling pathways or by combination with other anti-HER2 drugs or treatments (revised in [ 14 , 93 ]).…”

Antibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor Family in Cancers

“…3) The emerging resistance to ADC treatment is another hurdle to overcome. Studies have indicated that ineffective internalization and lysosomal trafficking or degradation of ADCs could be the major mechanism of resistance to T-DM1 ( Takegawa et al, 2017 ; García-Alonso et al, 2020 ; Díaz-Rodríguez et al, 2022 ). Required resistance to the free cytotoxic drug (DM1) through upregulation of drug efflux pumps or alternation of tubulins/microtubule-associated proteins, could also be responsible for resistance to T-DM1 ( García-Alonso et al, 2020 ).…”

“…Required resistance to the free cytotoxic drug (DM1) through upregulation of drug efflux pumps or alternation of tubulins/microtubule-associated proteins, could also be responsible for resistance to T-DM1 ( García-Alonso et al, 2020 ). In addition, mechanisms of resistance related to antibody (trastuzumab) may also contribute to T-DM1 resistance, including decreased expression of HER2, expression of truncated forms of HER2, or mutations in the ERBB2 gene ( Bon et al, 2020 ; Díaz-Rodríguez et al, 2022 ).…”