Research and Development Program for Innovative Biologics — Toward the creation of innovative high-performance biologics originating from Japan

The Japan Agency for Medical Research and Development (AMED) is implementing the "Research and Development Program for Innovative Biologics" under a five-year plan that began in 2024. This program aims to achieve practical "stage-up to clinical trials" in order to create innovative biologics originating from Japan. Nineteen projects are currently underway, and we will introduce a selection of the "raw gems of biologics" from among them in a series of installments.

Antibody-mimetic drug conjugate using duocarmycin

A new platform for selective drug delivery to target cells

We have developed a drug delivery system called the Cupid-Psyche system, based on the streptavidin-biotin interaction (said to be the strongest non-covalent interaction found in nature), which combines low immunogenicity with resistance to interference from endogenous biotin noise in the body. The Cupid-Psyche system consists of Cupid, a mutated streptavidin protein, and Psyche, a modified biotin-based small molecule. Simply mixing the two components generates a fully homogeneous conjugate in which Cupid and Psyche bind in a 1:2 ratio. In constructing this platform, we first used protein engineering to modify specific amino acid residues in the biotin-binding pocket of streptavidin so that its affinity for biotin falls below the detection limit (Cupid). This renders the system unaffected by endogenous biotin (vitamin B7), which is present in the body as a coenzyme. We then chemically modified the structure of biotin via organic synthesis so that it binds to the modified binding pocket of Cupid, and further dimerized it to enable bivalent binding, thereby achieving strong binding affinity (Psyche). By combining Cupid fused with an antibody targeting cancer antigens and Psyche linked to an anticancer drug, the drug can be selectively delivered to cancer cells. The Cupid-Psyche system has proven to be a powerful platform capable of carrying a wide range of payloads-including isotopes and photoactivatable agents-to various cancer cell targets, making it a versatile foundation for diverse anticancer strategies.

Duocarmycin (Duo), the payload used in this Research and Development Program for Innovative Biologics project, is a naturally derived antibiotic with extremely potent antitumor activity that exerts cytotoxicity at very low picomolar concentrations. Duo binds to the minor groove of the DNA double helix and alkylates DNA, thereby inhibiting replication and transcription and inducing cell death. Because of its high cell-killing capacity, direct use of Duo as a conventional anticancer drug results in excessive toxicity to normal cells and pronounced side effects. On the other hand, if a drug delivery system could be used to deliver Duo specifically to target cancer cells, it is expected to demonstrate high efficacy as a cancer therapeutic.

Based on the above, this research is advancing the development of Duo-HER2, a composite formulation of Duo-conjugated anti-HER2 antibody mimetic. To achieve this, we are using VHH-Cupid, an artificial antibody mimetic bearing a variable heavy chain of heavy chain-only antibodies (VHH) against HER2, which is an important antigen in solid advanced cancers with recurrence and metastasis. This is combined with Duo-Psyche, in which Duo-capable of killing cancer cells with an extremely small number of molecules-is linked to Psyche (figure). Our results to date have made it possible to supply Duo-Psyche in large quantities and in a stable manner. In mouse experiments, Duo-HER2 has achieved complete cancer eradication without causing side effects, and advantages over existing drugs are also becoming apparent. Going forward, we will further accelerate our research and work toward stage-up to clinical trials in humans. Our entire team is committed to this research so that we can deliver superior anticancer drugs to patients who are suffering from illness and their families as soon as possible.