Trials for bispecific antibodies in cancer immunotherapy

Yuhan's candidate product, acquired from ABL Bio, enters Phase 1 trial…Hanmi conducts research on its proprietary new drug

Korean biotech industry conducts active R&D…Tium Bio·ImmuneOncia conduct clinical trials

Yuhan, Hanmi Pharmaceuticals, and other domestic pharmaceutical and biotech companies have entered Phase 1 clinical trials of bispecific immuno-oncology drugs, delving into new drug development.

 

Bispecific antibodies are drugs that can simultaneously bind to two different antigens or two distinct antigen-binding sites on the same antigen.

 

Multispecific antibodies that target biomarkers simultaneously have the advantage of crossing the blood-brain barrier (BBB) by binding to receptors on its surface.

 

In particular, passage through the BBB is necessary for anticancer drugs to enhance drug permeability.

 

Recently, an increasing number of companies have been developing multispecific antibodies by combining antibodies that bind to antigens regulating immune cell activation with those that bind to tumor-specific antigens.

 

Yuhan·Hami enter phase 1 trials #iAccording to industry sources, on the 9th, Yuhan received IND approval from the Ministry of Food and Drug Safety (MFDS) for its bispecific antibody immuno-oncology candidate 'YH32364.' Introduced initially to Yuhan in 2018 from ABL Bio, YH32364 is now entering its first clinical study in humans.

 

This trial will assess the safety, tolerability, pharmacokinetics, and antitumor activity of YH32364 in patients with locally advanced or metastatic solid tumors that overexpress the epidermal growth factor receptor (EGFR).

 

YH32364 is designed as a bispecific antibody that simultaneously targets EGFR and 4-1BB.

 

EGFR is a well-known biomarker expressed in major solid tumors, including non–small cell lung cancer (NSCLC) and colorectal cancer.

 

By simultaneously targeting EGFR and T-cell activating 4-1BB, Yuhan aims to maximize the antitumor effect of this immuno-oncology candidate.

 

Hanmi Pharmaceuticals, in collaboration with Beijing Hanmi Pharmaceuticals, is currently conducting a Phase 1 clinical trial of the immuno-oncology candidate 'BH3120,' which targets both 4‑1BB and PD‑L1.

 

Cetuximab is an anticancer drug that targets the EGFR receptor and is used in the treatment of various cancers, including colorectal cancer, head and neck cancer, and lung cancer.

 

Yuhan expects YH32364, which activates immune cells through 4‑1BB action dependent on the tumor’s EGFR expression, will be effective against a broader range of EGFR‑expressing solid tumors than conventional anti‑EGFR monoclonal antibodies.

 

Hanmi Pharmaceuticals, in collaboration with Beijing Hanmi Pharmaceuticals, is currently conducting a Phase 1 clinical trial of the immuno-oncology candidate 'BH3120,' which targets both 4‑1BB and PD‑L1.

 

Hanmi Pharmaceuticals’ proprietary platform technology Pentambody was used in developing BH3120.

 

Pentambody is a next‑generation dual antibody platform technology that activates immune cells while attacking only the target cancer cells.

 

Because BH3120 activates 4‑1BB only in immune cells surrounding PD‑L1‑expressing tumor cells, it minimizes the toxic side effects of 4‑1BB and achieves long‑term anticancer effects that prevent recurrence.

 

In clinical trials, BH3120 demonstrated decoupling effects of immune activation between the tumor microenvironment and normal tissues, confirming its safety.

 

Hanmi Pharmaceuticals and Beijing Hanmi Pharmaceuticals also explore combining BH3120 with additional anticancer agents.

 

Active R&D for bispecific immune-oncology agents Korean biotech industry also focuses on bispecific antibody immune-oncology agents.

 

In addition to ABL Bio's YH32364 (ABL Bio candidate ABL104) transferred to Yuhan, it also has ABL501, which targets PD‑L1 and LAG‑3, and ABL503, which targets PD‑L1 and 4‑1BB.

 

ABL501 is a bispecific antibody designed to improve the low response rates of conventional immuno-oncology agents and treat patients with resistance by targeting two different immune checkpoint proteins, PD‑L1 and LAG‑3.

 

This candidate blocks the binding of LAG3-MHCII and PD‑1-PD‑L1, thereby preventing T cells from being inactivated by tumors.

 

ABL501 mechanism of action (Source=ABL Bio).

In preclinical studies, ABL501 demonstrated tumor-killing effects in NSCLC patient's tumor cells and in patients' peripheral blood organoids, compared to the conventional Tisentric agent.

 

Currently, ABL501 monotherapy is being studied in a dose-escalation Phase I trial as a monotherapy.

 

This clinical study is funded by the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare (MOHW) under the National New Drug Development Support Project.

 

ABL Bio is also conducting a Phase 1 trial of ABL503.

 

Clinical data showed that the administration of ABL503 has demonstrated antitumor efficacy and confirmed its safety profile.

 

Notably, among the patients who achieved a complete response (CR) or partial response (PR), some had previously shown resistance to or experienced recurrence after treatment with immunotherapies targeting PD‑L1.

 

Among 26 patients exposed to the effective dose, responses were observed in 7 patients.

 

The results showed that there was one CR and six PR.

 

Regarding safety, after administration of ABL503, some toxicities inherent to PD‑L1 and 4‑1BB targeted anticancer agents were observed; however, these were manageable with steroid treatment or temporary treatment interruption.

 

Tium Bio has confirmed the efficacy of the bispecific inhibitor TU2218 in preclinical studies.

 

TU2218 concurrently blocks transforming growth factor (TGF‑β) pathways, which is known to interfere with immuno-oncology activity and vascular endothelial growth factor (VEGF).

 

The process maximizes the efficacy of immuno-oncology agents.

 

In a breast cancer mouse model, TU2218, in combination with an anti‑PD‑1 agent, improved tumor growth inhibition compared to conventional chemotherapy.

 

In a colorectal cancer model, the potential of a triple combination therapy was demonstrated.

 

In a colorectal cancer model, the potential of a triple combination therapy was demonstrated.

 

The combination of TU2218, an anti‑PD‑1 agent, and an anti‑CTLA‑4 agent exhibited superior tumor growth inhibition compared to the control group receiving a placebo plus an anti‑PD‑1 agent and an anti‑CTLA‑4 agent.

 

The triple combination therapy containing TU2218 achieved an 84% tumor growth inhibition rate, compared to 70% in the control group.

 

Additionally, TU2218, in combination with an anti‑PD‑1 agent and Renbatinib, achieved a 99% tumor growth inhibition rate.

 

IMC-201, developed by ImmuneOncia, is a bispecific antibody independently created using CD47 and PD‑L1.

 

In preclinical studies, IMC-201 strongly bound to solid and hematologic cancer cells expressing CD47/PD‑L1, while selectively acting only on the cancer cells even under conditions where red blood cells and cancer cells were co‑cultured.

 

Furthermore, it exhibited higher macrophage-mediated phagocytosis compared to the parental antibody, IMC-002.

 

In particular, in a mouse tumor model of triple‑negative breast cancer, IMC-201 demonstrated more potent tumor inhibition than the combination of the parental antibodies IMC-002 and IMC-001.

 

ImmuneOncia is also developing the immuno‑oncology candidate IMC-002.

 

IMC-002 is designed to block CD47 on cancer cells and inhibit macrophage signaling.

 

In a study where IMC-002 was administered to 12 patients, no drug toxicity was observed at any dose level.

 

Among these 12 patients, 6 achieved stable disease (SD).

 

The company plans to determine the recommended Phase 2 dose based on the clinical findings from the Phase 1b study.