NMT Inhibitors and Next-Gen Nectin-4 ADCs a Field Ripe for Research – Part II

The field of oncology is advancing with the introduction of N-myristoyltransferase (NMT) inhibitors and next-generation Nectin-4-targeted antibody-drug conjugates (ADCs). Building on the significant progress made with topoisomerase 1 and FRα-targeted treatments, these innovations have further accelerated the momentum in ADC development. Recent developments include Myricx Bio’s innovative NMT inhibitors, demonstrating promising preclinical results as alternatives to topoisomerase inhibitors. Additionally, Corbus Pharmaceuticals’ CRB-701, a Nectin-4-targeted ADC, shows strong clinical trial outcomes. The industry is witnessing significant investments and strategic moves by major pharmaceutical companies, underscoring the growing impact and future potential of ADCs in cancer therapy.

Myricx Bio’s NMT inhibitors and Next-Gen Nectin-4-targeted ADCs an Alternative to Topo-1

Earlier in July, Myricx Bio Ltd. of London made headlines as a new player in the ADC arena, closing the largest series A funding for a European biotech this year with £90 million (US$115.4 million). The company aimed to advance ADCs with a novel approach to payload chemistry. In preclinical research, Myricx demonstrated that its N-myristoyltransferase (NMT) inhibitors induced complete and durable tumor regression at well-tolerated doses in models unresponsive to topoisomerase inhibitors. Additionally, researchers observed potent bystander activity and high efficacy in tumor-derived organoids across various antigen expression levels. Cancer cells frequently overexpress NMT, and tests on inhibitors in 700 human cancer cell lines revealed that 25% were highly sensitive to these compounds.

At the June meeting of the American Society of Clinical Oncology (ASCO) in Chicago, ADCs took center stage. Corbus Pharmaceuticals Holdings Inc., based in Norwood, Massachuesettes, presented its first-in-human study of the next-generation Nectin-4-targeted ADC CRB-701 for metastatic urothelial cancer, showing a 44% overall response rate (ORR) and a 78% disease control rate (DCR). In cervical cancer, the ADC achieved a 43% ORR and an 86% DCR at doses of 1.2 mg/kg or higher, with no dose-limiting toxicities up to 4.5 mg/kg. The phase I study targeted patients with advanced solid tumors who had failed or were intolerant to standard treatments. Corbus had licensed CRB-701 from CSPC Pharmaceutical Group in Hebei, China, for $7.5 million up front in February 2023. The ADC received IND clearance from the U.S. FDA, and significantly boosted the company’s stock. 

Big Pharma’s Moves in the ADC Game

In recent years, the ADC development landscape has witnessed significant investments from major biopharma companies, each vying for exclusive rights worth over $1 billion. Notably validating the ROR1 target, Boehringer Ingelheim GmbH acquired NBE Therapeutics AG for $1.4 billion in the fourth quarter of 2020, while Merck & Co. Inc. acquired Velosbio Inc. for $2.75 billion. Then in 2022, Eli Lilly and Co. secured a $1.75 billion deal with Immunogen Inc., while Celltrion Healthcare Inc. and Pinotbio Inc. closed a $1.24 billion agreement. Amgen Inc. partnered with Legochem Bioscience Inc. for $1.25 billion, and Janssen Biotech Inc. entered a $1.04 billion pact with Mersana Therapeutics Inc. Additionally, Astellas Pharma Inc. made a substantial move with Sutro for $1.4 billion.

The momentum continued into 2023, highlighted by Daiichi Sankyo Co. Ltd.’s monumental $22 billion pact with Merck & Co. Inc. for ADC development. Following closely, Systimmune Inc. and Bristol Myers Squibb Co. collaborated on an $8.4 billion bispecific ADC effort. Top mergers and acquisitions in the same year included Pfizer Inc.’s acquisition of Seagen Inc. for $43 billion and Abbvie Inc.’s purchase of Immunogen for $10.1 billion. Asian market interests were evident with Shanghai-based Duality Biologics Co. Ltd. also entering the fray with a $1.67 billion licensing deal with Biontech SE in April 2023. Then, ahead of Forseen’s transaction, Orion Holdings Inc. acquired a 25.73% stake in Ligachem Biosciences Inc. for $412 million in 2024, and Biotheus Inc. and Hansoh Pharmaceutical Group Co. Ltd. forming a $699 million partnership to develop bispecific ADCs for cancer. 

Understanding the Mechanisms: How NMT Inhibitors and Next-Generation Nectin-4 ADCs Revolutionize Cancer Therapy

N-myristoyltransferase (NMT) inhibitors are a class of targeted cancer therapies that block the enzyme N-myristoyltransferase, which plays a crucial role in adding myristoyl groups to proteins. This post-translational modification is essential for the proper function and localization of various proteins involved in cancer cell signaling and proliferation. Consequently, by inhibiting NMT, these drugs can disrupt the myristoylation process, impairing the function of oncogenic proteins and potentially inhibiting tumor growth. As a result, NMT inhibitors are under investigation for their potential to offer a novel approach to cancer treatment.

Next-generation Nectin-4-targeted antibody-drug conjugates (ADCs) enhance targeted cancer therapy by combining an antibody specific to Nectin-4 with a potent cytotoxic drug. Nectin-4, an adhesion molecule often overexpressed in cancers such as bladder and triple-negative breast cancer, serves as the target for these ADCs. Therefore, the antibody directs the ADC to cancer cells expressing Nectin-4, allowing precise delivery of the cytotoxic agent. Enhanced versions of these ADCs aim to improve targeting specificity, reduce off-target effects, and utilize more effective cytotoxic drugs, thereby increasing therapeutic efficacy and minimizing side effects compared to earlier versions.

The ADC sector is witnessing dynamic growth and strategic maneuvering in biotech, marked by major acquisitions, partnerships, clinical trials, and funding rounds. These developments highlight ADCs’ pivotal role in advancing targeted therapies, shaping oncology’s future.

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Author

Bernice Lottering