The abstract from AACR hides a new modality. Following yesterday’s TCE conjugated ADC, there is also the Triple-payload ADC project submitted by Araris. Currently, only the abstract has been released, indicating that this is an ADC molecule targeting Nectin-4, designed with MMAE and dual Topo1i as a triple payload. Below is the full abstract:Araris’s site-specific and one-step conjugation technology aims to generate stable, safe, and efficient ADCs without the need for antibody engineering prior to payload conjugation. We introduce a novel Nectin-4 targeted triple payload ADC that combines MMAE and two different topoisomerase 1 inhibitors (TOP1i, DAR2+2+2), aimed at treating various solid tumors expressing Nectin-4.With this novel ADC, our goals are 1) to effectively kill heterogeneous and resistant tumors by delivering multiple cytotoxic payloads to the same tumor cell,2) to control and limit bystander activity to avoid excessive toxicity,3) to maximize payload delivery through stable linker-payload conjugation, resulting in antibody-like ADC pharmacokinetic exposure profiles.The triple payload ADC shows high homogeneity and purity, with a DAR of 6, as expected. The ADC exhibits high stability under stress conditions, with no signs of aggregation, which we attribute to the hydrophilicity of the peptide-linker-payload design.In target-positive cancer cell lines, the ADC demonstrates high target-specific cytotoxic activity. It further shows excellent stability in mice, cynomolgus monkeys, and human serum, with no linker-payload decoupling or linker cleavage, and the DAR remains unchanged. Most importantly, the ADC is extremely stable in circulation, showing exposure profiles similar to that of the unmodified parent antibody in rodents. Notably, in dose-ranging studies, the tolerance in rats shows HNSTD exceeding 20 mg/kg (compared to Enfortumab vedotin (EV): 5 mg/kg). No significant skin or hematological toxicity was observed, indicating that the triple payload does not cause toxicity exceeding the single payload toxicity curve in rats. Surprisingly, in the receptor-overexpressing breast cancer SUM-190PT xenograft model, administration of the triple payload ADC at a single dose of 0.5 mg/kg on day 0 resulted in persistent complete tumor regression (over 100 days), indicating synergistic activity among different payloads.Interestingly, using MMAE (DAR2) and TOPi (DAR2+2) ADCs separately, each at a dose of 0.5 mg/kg, showed no response when combined, and Enfortumab vedotin (EV) also showed no response, which is currently the standard treatment for mUC targeting Nectin-4. Additionally, in the low Nectin-4 expressing TNBC PDX model, a dose of 2.5 mg/kg confirmed high anti-tumor activity, leading to significant and complete anti-tumor responses compared to EV and Sacituzumab govitecan (FDA-approved TNBC ADC).In summary, the first-in-class Nectin-4 targeted triple payload ADC demonstrates very high anti-tumor efficacy in CDX and PDX models and shows good tolerance in rats. We are the first to demonstrate that combining multiple payloads in a single ADC can produce synergistic effects in mouse models while still maintaining good tolerance.Last month, Araris was acquired by Japan’s Daicel Pharma. Currently, this project has not been mentioned in other contexts. Araris had previously acquired antibodies targeting Nectin-4 from ARS, which may be the source of the monoclonal antibody component of this ADC project. At last year’s AACR conference,Araris disclosed a dual payloadstrategy using two payloads based on irinotecan with different properties.The first has high cell permeability, producing bystander effects, while the second has low permeability, allowing it to accumulate within target cells.This dual approach can mitigate drug efflux pump-mediated resistance, enhancing efficacy even in resistant cells.Moreover, due to the relatively easy-to-understand mechanism of irinotecan, this dual payload configuration may have higher predictability. The triple payload is likely based on the previously reported dual Topo1i with an additional MMAE, still retaining high predictability characteristics.Related Articles:Dual payload ADC disclosed at AACRRoche takes the lead in the dual payload trendAraris launches dual payload ADC
