Release time：May 22, 2023
Recently, the preclinical study results of 9MW2821, the first domestically developed Nectin-4-targeting ADC by Mabwell, were published in the renowned journal "Molecular Cancer Therapeutics" under the American Association for Cancer Research (AACR). The paper comprehensively elaborated on the development and preclinical study results of 9MW2821 as a new generation Nectin-4-targeting ADC, and systematically compared it with the only approved Nectin-4-targeting ADC on the market (PADCEV, EV).
Nectin-4 is closely related to the progression and poor prognosis of malignant tumors. Enfortumab Vedotin (EV) is the first Nectin-4-targeting ADC approved by the US Food and Drug Administration (FDA) for the treatment of advanced urothelial carcinoma. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV. Ocular, pulmonary, and hematological toxic side effects are common in nectin-4-targeting therapy, which frequently results in dose reduction and/or treatment termination. These reasons may limit the wider use of Nectin-4-targeting therapy.
9MW2821 is a novel Nectin-4-targeting ADC based on inter-chain site specific conjugate technology, composed of specially designed linker, novel antibody molecule, and the cytotoxic drug MMAE. It not only has good tumor binding ability and target specificity, but also differs from existing Nectin-4-targeting ADC therapy (PADCEV, EV). It has more homogeneous composition, more stable structure, and superior tumor delivery ability.
In vitro cell experiments and animal studies have found that the unique structure of 9MW2821 brings the following significant characteristics:
9MW2821 enhances the antibody's internalization activity, exhibiting similar tumor internalization activity as EV in Nectin-4 high-expressing tumors and superior tumor internalization activity compared to EV in low-abundance tumors.
9MW2821 improves the plasma stability of the drug and significantly improves its pharmacokinetic (PK) characteristics. In PK studies, it had a higher intra-tumoral concentration of MMAE (9MW2821, Cmax: 106 pmol/ml; EV, Cmax: 76 pmol/ml; p＜0.01) and intra-tumoral exposure (9MW2821, AUC0-t: 2452 pmol/mL*h; EV, AUC0-t: 2116 pmol/mL*h; p＜0.05).
In the CDX models, 9MW2821 exhibit comparable activity as EV in urothelial carcinoma, and has superior tumor suppression effects in non-small cell lung cancer and breast cancer. In addition, the PDX models show that it has excellent tumor suppression effects in different tumors, including cervical cancer and lung cancer models, and also has certain tumor therapeutic effects in low- to medium-abundance solid tumors and large volume solid tumors.
9MW2821 has good drug safety, and toxicology studies have shown that it has milder skin toxicity, eye toxicity and gastrointestinal toxicity at equivalent doses.
9MW2821 is an ideal ADC with homogeneous drug-to-antibody ratio, tumor-specific properties, bystander killing effect, ideal efficacy in multiple solid tumors, and an acceptable therapeutic window. Based on the above study results, the company is conducting phase I/II clinical studies for 9MW2821 in multiple solid tumors and validating the related study results.
The novel Nectin-4-targeting ADC, developed independently based on the Mabwell ADC Platform and High-throughput Screening Platform, has applied for multiple patents for its antibody molecule, linker, drug molecule, and platform-related site-specific conjugation technology.
Currently, multiple clinical studies covering more than 10 types of tumors are being conducted. Preliminary data shows that at the recommended phase 2 dose (RP2D), among 12 evaluable subjects with urothelial carcinoma, the objective response rate (ORR) reached 50%, and the disease control rate (DCR) reached 100%; among 6 evaluable subjects with cervical cancer, the ORR reached 50%, and the DCR reached 100%. The expansion of multiple cohorts, including urothelial carcinoma, cervical cancer, prostate cancer, HER-2 negative breast cancer, and non-small cell lung cancer, is actively being pursued.
About Molecular Cancer Therapeutics
Molecule Cancer Therapeutics (an AACR journal, Print ISSN: 1535-7163, Online ISSN: 1538-8514) publishes translational research studies focused on the discovery and preclinical development of therapeutic agents for oncology. It is an authoritative journal in the ADC field.