On April 16, 2024 Mabwell (688062.SH), an innovation-driven biopharmaceutical company with entire industry chain, reported the preclinical research findings of three potential novel drug candidates in poster format at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, held from April 5 to 10, 2024 (Press release, Mabwell Biotech, APR 16, 2024, View Source [SID1234642111]).

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Poster Presentation

1. Disrupting IL-11/IL-11R signaling by an efficacious anti-IL-11 antibody 9MW3811 enhances T cell tumor infiltration and synergizes with anti-PD-1 therapies in vivo

Synopsis No.: 2365

The reported 9MW3811 is a high-affinity humanized neutralizing antibody against IL-11 independently developed by Mabwell, and has IND applications approved in China, the United States, and Australia, and its phase I clinical trials are ongoing in Australia and China.

As an important inflammation factor, IL-11 plays a significant role in the development and progression of fibrosis and tumor. Studies have shown that high expression of IL-11 is associated with the prognosis of various tumors such as lung cancer, hepatic cancer, and colorectal cancer. IL-11 not only promotes the growth of tumor cells through the STAT3 pathway but also has a significant impact on immune cells in the tumor microenvironment. 9MW3811 effectively blocks the formation of the IL-11/IL-11Ra/gp130 ternary complex by binding to IL-11, thereby inhibiting the activation of downstream signaling pathways. 9MW3811 has shown good anti-tumor therapeutic effects in multiple preclinical pharmacodynamic models, especially when used in combination with anti-PD-1 antibodies, it significantly promotes lymphocytic infiltration of CD8+ T cells, improves the T cell exhaustion caused by anti-PD-1 antibodies, upregulates the secretion of cytotoxic cytokines, thus exhibiting better combined anti-tumor effects.

2. 2MW4991, a novel ADCC-enhanced integrin αvβ8 blocker, exhibits high anti-tumor potency and was well tolerated in cynomolgus monkeys

Synopsis No.: 6349

The reported 2MW4991 is a high-specificity and high-affinity ADCC-enhanced antibody targeting integrin αvβ8. Integrin αvβ8 is an important activator of TGF-β, and specifically regulates the activity of TGF-β in immune cells. Studies have found that integrin αvβ8 is highly expressed in various tumors, and blocking αvβ8 can completely inhibit the release of TGF-β. 2MW4991 can completely block the release of TGF-β mediated by αvβ8, showing strong anti-tumor activity in various pharmacodynamic models such as CT26 and EMT6, and significantly promotes immune cell infiltration in tumors, greatly increasing the sensitivity of immune-excluded tumors to PD1 inhibitors. 2MW4991 has a significant synergistic effect when used in combination with PD1. The studies conducted in non-primate models have shown that 2MW4991 has good safety and metabolic profiles.

3. 2MW4691, a novel CCR8/CTLA-4 bispecific antibody, displays potent anti-tumor efficacy by specifically depleting tumor-infiltrating Tregs and blocking CTLA-4 signaling on CD8+ T cells

Synopsis No.: 6350

The reported 2MW4691 is an ADCC-enhanced bispecific antibody targeting CCR8/CTLA-4. Targeting CTLA-4 has a strong anti-tumor effect, but its clinical application is limited due to strong side effects. CCR8 is a specific marker of tumor-infiltrating Tregs, and is almost not expressed in other immune cells and peripheral Tregs. Single-cell sequencing analysis of Treg cells infiltrating various tumors found that CCR8 is expressed in a small subset of Treg cells infiltrating tumors, and CTLA-4 is widely expressed in Treg cells and CD8+ T cells. 2MW4691 retains high affinity targeting CCR8 and attenuated CTLA-4-binding and -blocking activity, specifically eliminating Treg cells infiltrating tumors. Due to the lower CTLA-4 expression in the peripheral tissues, 2MW4691 only blocks the immunosuppression mediated by CTLA-4 signaling on peripheral CD8+ T cells. 2MW4691 demonstrates strong anti-tumor activity in preclinical CCR8 single transgenic animal models, CTLA-4 single transgenic animal models, and double transgenic animal models, and has shown good metabolic activity and safety in primate animals.