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Apr 05, 2024
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Nectin-4, despite being a well-established oncology target, is currently underutilized in drug development compared to HER2, TROP2, and Claudin18.2. However, its significant potential is underscored by its prevalent overexpression in various cancer types, such as pancreatic, ovarian, cervical, head-and-neck, breast, lung, and urothelial cancers.
As a cell adhesion molecule, Nectin-4 facilitates tissue growth and is selectively upregulated in cancer tissues, making it an attractive candidate for targeted cancer therapies. Despite limited attention from pharmaceutical companies, the development of drugs targeting Nectin-4 holds promising market prospects, necessitating further research and clinical exploration to harness its full therapeutic potential.
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ADCs targeting Nectin-4 combine a monoclonal antibody that precisely binds to cancer cells expressing Nectin-4 with a potent cytotoxic agent, causing the targeted cancer cells’ death. This focused strategy lowers systemic toxicity and increases the therapeutic index.
PADCEV (enfortumab vedotin), jointly developed by Astellas and Seagen (owned by Pfizer), became the first Nectin-4 ADC approved for the treatment of advanced bladder cancer in 2019.
Many companies are working in this area to optimize Nectin-4’s potential as a tumor target beyond urothelial malignancies and to overcome the therapeutic window constraints, providing patients with advanced or resistant disease with new hope. With further development, Nectin-4-targeted ADCs have the potential to revolutionize cancer treatment by offering new therapeutic alternatives that are both safe and effective. Few of the potential candidates in this area are being discussed here.
ADRX-0706 is a next-generation ADC with a drug-antibody ratio of 8, that targets nectin-4. Using a patented cleavable linker, an optimized tubulin inhibitor payload (AP052) is connected to a unique completely human IgG1k monoclonal antibody to form ADRX-0706. ADRX-0706 provides a strong binding affinity and selective cytotoxicity in Nectin-4-expressing tumor cells.
Based on preclinical data, ADRX-0706 provides a promising cancer therapy designed with an improved bystander effect, allowing it to regress tumors even in cases of heterogeneous Nectin-4 expression. It demonstrated superior efficacy over conventional treatments in multiple mouse xenograft models of other indications apart from bladder cancer. In a mouse trial with patient-derived cervical cancers, ADRX-0706 achieves a remarkable 73% ORR.
Notably, ADRX-0706 also shows a significantly lower risk of peripheral neuropathy compared to conventional treatments, as evidenced by in vitro studies. The conventional treatment enfortumab vedotin (EV) displays a substantial decrease in neurite outgrowth, ADRX-0706 demonstrates no adverse impact at concentrations up to 1mg/ml, indicating a significantly reduced risk of peripheral neuropathy in human patients.
Moreover, in preclinical repeat dose toxicology studies, ADRX-0706 achieves the Highest Non-Severely Toxic Dose (HNSTD) of 18mg/kg, well above therapeutic exposures observed in mouse pharmacology studies. This substantial increase in the therapeutic index compared to conventional treatments underscores the potential of ADRX-0706 as a transformative therapy in cancer treatment.
In essence, the clinical assessment of ADRX-0706, a next-generation anti-Nectin-4 ADC, is supported by its remarkable selectivity and potent anti-tumor efficacy across various cancer types, alongside its extensive preclinical therapeutic range. Presently, ADRX-0706 is undergoing Phase Ia/b trials (NCT06036121) targeting specific advanced solid tumors.
LY4052031 is a novel anti-Nectin-4 ADC with a novel topoisomerase I (TOPO 1) inhibitor drug payload. The TOPO inhibitor payload-based ADCs offer distinct advantages over microtubule payload-based counterparts, such as a different toxicity profile and unique susceptibility to resistance mechanisms like P-gp mediated drug efflux. LY4052031 comprises a fully human monoclonal anti-Nectin-4 antibody conjugated to the novel TOPO 1 inhibitor via a cleavable peptide linker at a homogeneous drug antibody ratio (DAR) of 8:1.
In vitro studies demonstrate that both LY4052031 and its unconjugated parental antibody bind specifically to Nectin-4 expressing cell lines and are efficiently internalized. LY4052031 exhibits potent cytotoxicity against tumor cells expressing varying levels of Nectin-4. Moreover, its bystander activity on antigen-negative cells co-cultured with antigen-positive cells surpasses that of the clinical benchmark, enfortumab vedotin-ejfv. In vivo studies using xenografts expressing low to high levels of Nectin-4 reveal significant tumor growth inhibition following LY4052031 monotherapy.
Overall, LY4052031 demonstrates remarkable specificity, selectivity, potency, and efficacy as a next-generation therapy for Nectin-4-positive tumors. We plan to submit an IND application in 2024.
IPH45 represents a novel topoisomerase I inhibitor ADC designed to target Nectin-4 with an enhanced therapeutic index. This ADC offers the potential for a broader therapeutic index compared to EV, alongside improved safety and dosing protocols. Moreover, it demonstrates the capacity to overcome primary and secondary resistance to EV or other Nectin-4 ADCs currently under development. As IPH45 advances toward clinical trials, its distinctive profile will undergo evaluation for its translatability into enhanced patient outcomes across various indications.
Based on a September 2023 press release, innate pharma proprietary nectin-4 targeted antibody-drug conjugate, IPH45 is progressing towards a Phase I clinical trial. Innate Pharma will present its clinical data at AACR 2024.
CNTY-107 is a Nectin4-targeting IPSC-derived cell therapy for the treatment of Nectin4-expressing solid tumors.CNTY-107, harnesses the power of engineered immune cells, particularly T cells, to target Nectin-4-expressing cancer cells with precision and efficacy. By leveraging the body’s immune system, CNTY-107 offers a personalized approach to cancer treatment, showing immense promise in revolutionizing the way we combat cancer.
CNTY-107 is a first-in-class iPSC-derived Nectin-4 CAR gamma delta T-cell therapy product candidate that will be engineered with multiple features to provide several mechanisms for tumor killing.
CNTY-107 is being prioritized by Century Therapeutics for advancement in Nectin-4+ tumors as part of the company’s internal portfolio restructuring and capital allocation strategy. This strategic move aims to focus resources on programs with the highest potential for success, including CNTY-107.
For more information, refer to Delveinsight’s Urothelial Carcinoma Market Insight, Epidemiology And Market Forecast – 2034 Report.
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