AP Biosciences is building the protocol around one key objective: confirm that conditional CD137 agonism, a tumor-restricted T-cell costimulation, can be delivered safely in patients whose HER2-positive solid tumors express the p95HER2 variant, a truncated, drug-resistant form of HER2. To that end, it recently dosed the first patient in the Phase 1/2 trial of its T-cube bispecific, AP402.
According to vice president of antibody discovery Jhong-Jhe “JJ” You, Ph.D., the core concept is that CD137 activation is triggered only when the antibody also binds to the tumor target, providing spatial control intended to minimize systemic cytokine release. “CD3 [a protein complex found on the surface of T-cells] can trigger widespread immune activation and lead to serious side effects like cytokine storm,” You said. “Our T-cube™ platform avoids that by using CD137, which only activates the T-cell when it also binds to the tumor-specific antigen. That means the immune response stays focused in the tumor, reducing off-target effects and improving safety.”
In a nutshell, the T-cube platform creates bispecific antibodies designed to conditionally activate T-cells via the CD137 co-stimulatory receptor. It thus achieves spatial control over the immune response primarily within the tumor microenvironment.
Phase 1 trial focused on safety and biomarkers
To translate these preclinical safety observations into the clinic, the Phase 1 dose-escalation stage will monitor patients receiving increasing doses of AP402. It will move toward exposures guided by preclinical data which, according to You, showed significant T-cell activity within the tumor while systemic markers remained low.
These biomarkers will be validated in the company’s upcoming AACR 2025 poster presentation on April 29. In the study, investigators dosed humanized mice bearing antigen-positive xenografts with escalating single injections of the bispecific and measured serum cytokines, tumor-infiltrating CD8 T cells, and liver enzymes.
These non-clinical findings support the central safety thesis: localized CD137 stimulation aims to avoid the systemic side effects, such as cytokine release syndrome, observed with other immune activation approaches. ‘Our T-cube platform avoids [the widespread activation seen with some engagers] by using CD137, which only activates the T cell when it also binds to the tumor-specific antigen,’ You elaborated. ‘That means the immune response stays focused in the tumor, reducing off-target effects and improving safety.
Preclinical data informs dosing strategy
The team’s primary goal is to identify a recommended phase 2 dose (RP2D). This dose should preserve the avidity-driven activity inherent to the bispecific antibody design without provoking dose-limiting cytokine release syndrome (CRS). Preclinical data suggest the bispecific’s 2 + 2 valency can deliver high-avidity tumor binding while keeping safety within manageable limits.
The underlying technology traces back to two in-house platforms: the Omni-Mab human antibody library and the T-cube bispecific engine. The Omni-Mab platform provides the company’s fully human antibody library, while T-cube uses a unique CD137 antibody identified by the company, paired with a tumor-associated antigen binding fragment. This arrangement ensures that T-cell costimulation is effectively “tethered” to the tumor microenvironment. The Omni-Mab library contains more than 100 billion sequences and has produced binders with sub-nanomolar affinity.
Building the next wave of candidates
AP Biosciences is also advancing other candidates, including planning an IND filing later this year for a T-cube bispecific antibody targeting pancreatic and esophageal cancer. You elaborated slightly on this next step during the interview, stating, “Later this year, we are planning to file an IND…for another new bispecific antibody derived from T-cube, targeting pancreatic and esophageal cancer.”
AP Biosciences includes a growing roster of clinical programs. IBI302, a VEGF/Complement bispecific, is in Phase 3 (NCT05972473) for wet AMD and DME with partner Innovent. AP505 (PD-L1 × VEGF) has completed Phase 1 and is enrolling Phase 2 in collaboration with Tasly in China. AP203 (PD-L1 × CD137) was the first T-cube molecule to reach the clinic; Phase 1 is under way in Taiwan and the U.S., with a Phase 2 expansion planned for NSCLC, HNC and ESCC.
Financing for the clinical push is supported by a $38 million Series D round closed in 2024. You stated the funding enables the company to advance its wholly-owned clinical programs like AP402 and AP203, file new INDs, invest in new modalities, and expand platform capabilities.
Assuming no unexpected safety signals, the company anticipates initial dose-escalation data towards the end of 2025 or in early 2026 and to open expansion cohorts in tumor types that overexpress its chosen antigen shortly after.
The company is also exploring new modalities, such as conjugating cytotoxic payloads to create bispecific antibody-drug conjugates (ADCs). This exploration into ADCs aligns with the broader investment strategy “We are also investing in new modalities, like bispecific antibody ADCs, and expanding the capability of our Omn-iMab platform.”
You reiterated the APBio’s mission is to pioneer next-generation multispecific antibodies to bring real change for patients with hard-to-treat cancers. The company was founded in 2013 “with the clear mission to pioneer next-generation multispecific [antibodies]… to bring a real change for patients with hard-to-treat cancer,” he said.
APBiosciences was founded by Jeng Her, Ph.D., a KaloBios co-founder. IBI302 was the first program, predating the T-cube portfolio. As JJ You recalled, it was “kind of our first product… developed in the US by Dr. Her… around probably 2012 or 2013… kind of the first in class drug for wet MD… differentiated to other, the benchmark antibody, like[Eylea].”
The company chalks up its support in part to Taiwan’s biotech ecosystem, which offers local talent, clear regulations and government support, to run R&D at home while partnering internationally. Taiwan remains a robust investor in R&D and is a world leader in the semiconductor industry. You noted the government’s approach: “the Taiwan government has tried to graft the semiconductor model onto the biotechnology industry.” As he put it more broadly: “Taiwan has been incredible, so supportive the environment for biotech innovation… It’s a great place to bring innovation across the Asia and the West.”
Filed Under: Biotech, Oncology
