Abstract 189P
Background
HER2 overexpression is observed across various tumor types, including breast, gastric cancer, and gastroesophageal junction adenocarcinoma. Enhertu (Trastuzumab deruxtecan, DS-8201a), an ADC targeting HER2, has shown impressive efficacy in treating HER2-positive cancers. However, Enhertu has encountered payload deruxtecan related resistance in clinical settings. Here, we prepared NC18, a novel HER2-targeting ADC comprising a HER2 -targeted humanized monoclonal antibody conjugated to AF-HEA, a tubulin inhibitor, via a polymer linker. NC18 exhibits promising in vivo anti-tumor activity against Enhertu -induced resistant CDX model.
Methods
In vivo anti-tumor activity was assessed using xenograft models in NOD SCID mice implanted with NCI-N87 cells obtained from ATCC and Enhertu-resistant NCI-N87-R-Enhertu cells, which were developed through continuous Enhertu exposure.
Results
In the NCI-N87 CDX model, both Enhertu (3 mg/kg) and NC18 (3 mg/kg) significantly inhibited tumor growth, with TGI% values of 65.42% and 97.58% on day 28 post-dose, respectively. In the NCI-N87-R-Enhertu CDX model, NC18 showed superior anti-tumor efficacy with a TGI% of 92.20% on day 28, compared to Enhertu’s 11.92% at the same dose. Notably, all treatments exhibited good tolerability with no observed deaths throughout the treatment period. WuXi APP Tec identified that upregulation of AKR1C, ALDH3A1 and UGT1A6 genes in NCI-N87-R-Enhertu cells, rather than changes in HER2 expression or multidrug transporters, led to Enhertu resistance by affecting Dxd metabolism and reducing the cytotoxic effect. Additionally, NC030-107, another ADC with the same payload as NC18 and different linker, also displayed potent killing effects on varies of Enhertu-resistant tumor cells in vitro, including NCI-N87-R-Enhertu and HCC1954-R-Enhertu cells, showing relative activity 30 times and 400 times higher than Enhertu, respectively. NC030-107 is currently undergoing preclinical evaluation.
Conclusions
In summary, FDA and CDE have approved NC18 for clinical trials in HER2-positive/expressing advanced solid tumors, and the findings in this paper strongly support an expanded patient population with Enhertu resistance.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Novacyte Therapeutics Company, Ltd.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.