Abstract 2635: N-Myristolytransferase (NMT) inhibitors as novel potent payloads for antibody drug conjugates

Abstract

Abstract Introduction: There is a need for ADC payloads with an improved therapeutic index, consequently we have coupled potent and selective inhibitors of NMT to trastuzumab to test their potential in both in vitro and in vivo models. Experimental Procedures: A highly potent NMT inhibitor was conjugated to trastuzumab using two different linkers to produce an ADCs with a DAR of 5. These ADCs were tested in vitro in cell killing studies using Her2+ and Her2- cell lines and subsequently tested in vivo in breast cancer and gastric cancer xenografts. Results: Our first Trastuzumab-NMT inhibitor ADC (MYX2449) caused cell death in Her2+ BT474 cells with an EC50 of 0.2nM and peaking after 8 days of incubation, but was inactive against Her2- cells MCF7 at concentrations up to 100nM. MYX2449 was tested in a BT474 xenograft implanted orthotopically in the mammary gland fat pad and compared to Trastuzumab and vehicle controls. Both antibodies were dosed IV once a week for four weeks at 2.5 and 5 mg/Kg. MYX2449 therapy at 2.5mg/Kg resulted in a partial response (TGI 55% on day 21) and 5mg/Kg resulted in a TGI of 108% on day 21 with 7/10 mice having undetectable tumor by day 33 with no significant body weight loss during the study. Trastuzumab resulted in no response at 2.5mg/Kg a partial response at 5mg/Kg. MYX2449 was subsequently tested in a gastric cancer xenograft, NCI-N87 inoculated subcutaneously and compared to an NMT inhibitor conjugated isotype control and to Trastuzumab and Trastuzumab deruxtecan. All antibodies were dosed IV at 2.5mg/Kg or 5mg/Kg on day 1 and day 8. Day 21 TGI for the 5mg/Kg Trastuzumab group was 193%, for the 5mg/Kg Trastuzumab-deruxtecan group TGI was 154% and for the 5mg/Kg MYX2449 group TGI was 280%. In the MYX2449 5mg/Kg group, 6/10 mice had undetectable tumors on day 21 and 2/10 of the MYX2449 2.5mg/Kg group. Mean body weights of all groups had increased by day 21. Conclusions: Potent small molecule inhibitors of NMT can be readily conjugated to therapeutic monoclonal antibodies to generate novel highly effective and well tolerated ADC payloads. NMT inhibitors represent a totally novel class of ADC payloads that exploit cancer cell dependency on myristloylated proteins. The potential of this novel mechanism to deliver high efficacy with better TI is currently being investigated in preclinical models. Examples of Myricx patented chemical structures will be disclosed. RS, ND, FF and RC are employees of Myricx Pharma.JW, FO and ET are funded by Myricx Pharma.ET is a board member and founder of Myricx Pharma. Citation Format: Robin A. Carr, Roberto Solari, Nikki D'Arcy, Ed Tate, Josephine Walton, Folake Orafidiya. N-Myristolytransferase (NMT) inhibitors as novel potent payloads for antibody drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2635.