[Fam-] trastuzumab deruxtecan (DS-8201a)-induced antitumor immunity is facilitated by the anti–CTLA-4 antibody in a mouse model

Abstract

[Fam-] trastuzumab deruxtecan (DS-8201a) is a HER2 (ERBB2)-targeting antibody-drug conjugate, composed of a HER2-targeting antibody and a topoisomerase I inhibitor, exatecan derivative, that has antitumor effects in preclinical xenograft models and clinical trials. Recently, [fam-] trastuzumab deruxtecan was reported to enhance antitumor immunity and was beneficial in combination with an anti–PD-1 antibody in a mouse model. In this study, the antitumor effect of [fam-] trastuzumab deruxtecan in combination with an anti–CTLA-4 antibody was evaluated. [Fam-] trastuzumab deruxtecan monotherapy had antitumor activity in an immunocompetent mouse model with EMT6 human HER2-expressing mouse breast cancer cells (EMT6-hHER2). [Fam-] trastuzumab deruxtecan in combination with the anti–CTLA-4 antibody induced more potent antitumor activity than that by monotherapy with either agent. The combination therapy increased tumor-infiltrating CD4+ and CD8+ T cells in vivo. Mechanistically, cured mice with treatment of [fam-] trastuzumab deruxtecan and an anti–CTLA-4 antibody completely rejected EMT6-mock cells similar to EMT6-hHER2 cells, and splenocytes from the cured mice responded to both EMT6-hHER2 and EMT6-mock cells as measured by interferon-gamma release. Taken together, these results indicate that antitumor immunity is induced by [fam-] trastuzumab deruxtecan and is facilitated in combination with anti–CTLA-4 antibody.

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

“…When it comes to the desired properties of drugs, it is important to have optimal stability properties while the drug moves through the human plasma, along with efficient target-specific drug release [42,[56][57][58][59][60][61][62]. Out of the above mentioned ADCs, preclinical experiments on animal models are reported only for MEDI4276, RC48, ARX 788, DS-8201, and SYD 985, and hence more in vitro and in vivo experiments are imperative in this area [59,61,62,66]. Similarly, mathematical models that depict the dynamics of these novel drugs, as well as many of FDA-approved anti-HER2 agents are yet to be devised.…”

Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance

“…Combinatorial use of ADCs with immune checkpoint inhibitors is another approach to enhancing ADC efficacy. This approach has been pursued as a means to improve overall survival of patients with various cancers 21 – 23 . Recently, multi-loading linkers have been proposed as a novel strategy for incorporating two distinct payload molecules into single monoclonal antibodies (mAbs) 24 – 26 .…”

Advances in epidermal growth factor receptor specific immunotherapy: lessons to be learned from armed antibodies

“…On the other hand, a DAR of 8 showed to cause ADC deterioration, increase premature clearance from bloodstream and aggregation capacity, which induces an immunogenic reaction as a result of the hydrophobic nature of the payloads, while reducing their stability under stress conditions [31]. Contradicting results using similar DAR (8) were recently published by Iwata et al (2018 and 2019), showing the antitumor efficacy of trastuzumab deruxtecan (Humanized anti-hHER2 conjugated with the topoisomerase I inhibitor exatecan derivative DS-8201) using a mouse model of colon and breast cancers overexpressing HER2 receptor [135,136]. DS-8201 was exerting its therapeutic efficacy by specifically killing HER2 expressing tumors and increasing tumor infiltrating dendritic cells, CD4 + and CD8 + T-cells in vivo [137,138].…”