World ADC 2023: Preclinical Data Validates NMTi as a Novel ADC Payload Class

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Results from a preclinical efficacy studies validates the N-Myristoyltransferase inhibitor (NMTi) payload platform, being developed by UK-based Myricx Bio, as a novel class of payloads for ADCs.  In preclinical studies NMTi payloads demonstrated complete tumor regressions across a range of solid tumor xenograft models for NMTi-ADCs targeting three clinically validated tumor-associated antigens (B7-H3, TROP2 and HER2).[1]

N-myristoylation (NMT) is an enzyme that adds a specific lipid modification to a number of protein targets key to cancer cell survival.

NMT ensures the proper function and intracellular trafficking of proteins. Many proteins involved in a wide variety of signaling, including cellular transformation and oncogenesis, are myristoylated.[2]

The myristoylation of proteins is catalyzed by the ubiquitously distributed eukaryotic enzyme N-myristoyltransferase (NMT).  Researchers found that NMT activity is higher in colonic epithelial neoplasms than in normal-appearing colonic tissue and that the increase in NMT activity appears at an early stage in colonic carcinogenesis.

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Elevated expression and activity of NMT is observed to varying degrees in a variety of tumor types. including colon cancer, gallbladder carcinoma, and lung and breast tumors. In addition, elevated levels of NMT in tumors is associated with poor survival. [3]

Myricx Bio is advancing a pipeline of ADCs to address serious unmet needs in oncology based on its NMT inhibitor (NMTi) payload chemistry platform and has demonstrated excellent preclinical efficacy and safety across multiple solid tumor associated antigens and cancer cell types.

Encouraging initial non-human primate tolerability in vivo efficacy data for its NMTi-ADC platform and pipeline will be presented at the 14th Annual World ADC Conference in San Diego, CA, being held October 16 – 19, 2023.

NMT inhibitors
Myricx’s payload platform is based on proprietary potent small molecule NMT inhibitors (NMTi). In the poster presentation Myricx Bio reported data for three NMTi-ADCs in its pipeline. These comprise B7-H3-NMTi, TROP2-NMTi, and HER2-NMTi.

  • B7-H3-NMTi demonstrated complete and durable tumor regressions in multiple models of aggressive prostate cancer refractory to Topo1i-based ADCs. Initial toxicology is currently under evaluation in non-human primates.
  • TROP2-NMTi also demonstrated complete and durable tumor regressions in breast cancer models refractory to Topo1i-based ADCs; including the ability to regress large and established tumors that had prior exposure to a Topo1i-based ADC.
  • HER2-NMTi demonstrated complete efficacy, and an encouraging tolerability profile in rodents and non-human primates. In addition, it showed potent bystander activity, and efficacy in patient-derived xenograft (PDX) organoid models with a broad range of antigen expression levels.

“The preclinical data generated by our three NMTi-ADCs give us confidence that the NMTi payload platform has the potential to deliver an important new ADC payload class in the treatment of solid tumors,” noted Dr Robin Carr, Chief Executive Officer at Myricx Bio

“We are looking forward to advancing our pipeline of ADCs and generating clinical data,” he concluded.

Myricx Bio is spin out from Imperial College London and the Francis Crick Institute. The company focuses on the discovery and development of a completely novel class of payloads for antibody-drug conjugates (ADCs),

Reference
[1] N-Myristoyltransferase (NMT) inhibitors as completely novel payloads for Antibody Drug Conjugates, deliver extensive tumor regression at well tolerated doses. [Download Poster]
[2] Shrivastav A, Selvakumar P, Bajaj G, Lu Y, Dimmock JR, Sharma RK. Regulation of N-myristoyltransferase by novel inhibitor proteins. Cell Biochem Biophys. 2005;43(1):189-202. doi: 10.1385/CBB:43:1:189. PMID: 16043893.
[3] Wang H, Xu X, Wang J, Qiao Y. The role of N-myristoyltransferase 1 in tumour development. Ann Med. 2023 Dec;55(1):1422-1430. doi: 10.1080/07853890.2023.2193425. PMID: 37140999; PMCID: PMC10161948.

Featured images courtesy of World ADC San Diego 2020.

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