Adagene and Incyte partner on bispecific immunotherapy combo for MSS CRC

Adagene Inc., (Nasdaq: ADAG), a clinical-stage biotech operating out of Suzhou, China, and San Diego, and Incyte (Nasdaq: INCY), a Delaware-based biopharma, have entered a clinical collaboration to evaluate muzastotug (ADG126) in combination with INCA33890, Incyte’s TGFβR2 x PD-1 bispecific antibody, in patients with microsatellite stable colorectal cancer (MSS CRC). The collaboration targets a patient population with limited therapeutic options, specifically those in the third-line setting with or without liver metastases.

Financial terms were not disclosed. As a clinical supply and study conduct arrangement, Incyte will sponsor and conduct the Phase I study, while Adagene will provide clinical trial supply of muzastotug.

The Phase I study is expected to initiate in 2026. The trial will include a dose escalation portion evaluating safety and tolerability, followed by an efficacy expansion cohort in patients with chemotherapy-refractory MSS CRC with and without liver metastases.

The mechanistic rationale

MSS CRC treatment has remained one of oncology’s more intractable challenges. The disease subtype, which accounts for the substantial majority of metastatic colorectal cancer cases, is characterized by low tumor mutational burden and an immunosuppressive tumor microenvironment that renders it largely unresponsive to anti-PD-1 and anti-PD-L1 monotherapy. The presence of liver metastases further compounds the therapeutic difficulty, as the liver is a site of systemic immune tolerance and is associated with particularly poor prognosis.

The combination being evaluated in this collaboration addresses three distinct immunosuppressive mechanisms simultaneously. Muzastotug, a masked anti-CTLA-4 antibody built on Adagene’s SAFEbody precision masking technology, is designed to deplete regulatory T cells and restore T cell priming within the tumor microenvironment while limiting the systemic immune activation that has historically constrained conventional CTLA-4 inhibitors. The SAFEbody platform incorporates a masking peptide that shields the antibody’s binding domain in normal tissue and is preferentially cleaved in the tumor microenvironment, enabling tumor-localized pharmacological activity.

Bispecific antibody INCA33890

INCA33890, Incyte’s TGFβR2 x PD-1 combination therapy asset, simultaneously targets two additional axes of immunosuppression. PD-1 blockade reinvigorates exhausted effector T cells, while TGFβR2 inhibition addresses the stromal and cytokine-mediated barriers that prevent immune cell infiltration and activity in immunologically cold tumors. As a monotherapy, INCA33890 has demonstrated clinical activity in both immune checkpoint-sensitive and checkpoint-insensitive cancers, including MSS CRC with and without liver metastases, according to Incyte.

The resulting triplet mechanism — CTLA-4 blockade via muzastotug ADG126, PD-1 inhibition, and TGFβ pathway suppression via INCA33890 — reflects a hypothesis that coordinated attack across priming, effector, and stromal compartments of the immune response may be required to generate durable anti-tumor activity in this indication.

Muzastotug’s expanding combination program

The collaboration with Incyte represents the second instance in which muzastotug has been paired with a PD-1-based bispecific antibody. Adagene previously announced a combination study evaluating muzastotug alongside Sanofi’s SAR445877, a PD-1 x IL-15 fusion protein, in adults with advanced solid tumors. The company has characterized muzastotug as a potential backbone immunotherapy for next-generation combination regimens, citing its wider therapeutic index relative to conventional anti-CTLA-4 agents as a feature that enables its use in multi-agent settings where cumulative toxicity is a practical constraint.

Muzastotug carries FDA Fast Track designation and is currently in Phase Ib/II and Phase II clinical studies in combination with pembrolizumab, Merck’s anti-PD-1 therapy, in MSS CRC patients without liver metastases. A randomized Phase II study in that population is also underway, designed to identify the optimal dose for advancement into a Phase III registration trial. Prior data from the pembrolizumab combination have shown overall response rates and durable responses in third-line MSS CRC patients without liver metastases, according to Adagene.