Akeso, Inc. has dosed the first patient in a Phase 2 clinical trial evaluating AK146D1, its internally developed TROP2/Nectin-4 bispecific Antibody-Drug Conjugate (bsADC), in combination with ivonescimab, a PD-1/VEGF bispecific antibody, for the treatment of advanced breast cancer.

The Phase 2 AK146D1-202 study is designed to assess the potential of Akeso’s ‘IO2.0 + ADC2.0’ treatment strategy, with a particular focus on first-line treatment of hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer and Triple-Negative Breast Cancer (TNBC).

Breast cancer remains one of the most common cancers globally, with approximately 2.3 million new cases diagnosed each year. While advances in precision medicine, immunotherapy and Antibody-Drug Conjugates (ADCs) have improved outcomes for certain patient populations, treatment resistance, tumour heterogeneity and safety limitations continue to create significant unmet needs.

The challenges are particularly pronounced among patients with PD-L1-negative disease or those who develop resistance to anti-PD-1 therapies. Meanwhile, the therapeutic window of conventional ADCs can limit their efficacy and the number of treatment lines available to patients.

Akeso believes combining ivonescimab with AK146D1 could offer a complementary approach by integrating immune-based tumour control with targeted delivery of an ADC. Ivonescimab is a PD-1/VEGF bispecific antibody that has demonstrated clinical activity against PD-1 inhibitor-based therapies across multiple Phase 3 studies, while AK146D1 is a next-generation ADC candidate designed to target both TROP2 and Nectin-4.

According to Akeso, AK146D1 has demonstrated potent antitumour activity and a favourable safety profile in early clinical studies. The company is evaluating whether its combination with ivonescimab can enhance treatment efficacy while maintaining a manageable safety profile.

The programme forms part of Akeso’s broader ‘IO2.0 + ADC2.0’ strategy, which combines next-generation immuno-oncology agents with ADCs to address multiple mechanisms of tumour growth and resistance.

Akeso currently has two approved bispecific antibodies for cancer treatment and is evaluating ivonescimab and cadonilimab in combination with its proprietary next-generation ADC candidates. The company is also developing a pipeline of ADC programmes, including AK146D1, AK138D1, AK157D1 and AK158D1, a bispecific ADC.

These candidates are being designed to address limitations associated with earlier-generation ADCs, including narrow therapeutic windows and treatment-related safety concerns.

Beyond AK146D1, Akeso is conducting a Phase 1b/2 study evaluating its next-generation HER3 ADC, AK138D1, in combination with ivonescimab. The company is also advancing a Phase 3 study of an ivonescimab-based combination as a first-line treatment for TNBC, following encouraging Phase 2 data in breast cancer.

Akeso’s “IO2.0 + ADC2.0” strategy is intended to leverage multi-target and multi-mechanism combinations across different breast cancer subtypes and treatment settings. The company aims to develop combination regimens that can improve clinical outcomes, address treatment resistance and expand therapeutic options for patients with advanced cancers.

The initiation of the AK146D1-202 Phase 2 study marks another step in Akeso’s efforts to advance next-generation immuno-oncology and ADC combinations across high-incidence cancers, with breast cancer emerging as a key area of clinical development.