Antibody–cytokine fusion proteins

The bispecific/trispecific TCE platform

The PROTiNb (proteolysis targeting intra-nanobody) platform

Antibody discovery platform

Antibody–cytokine fusion proteins

Currently, about 70% of cancer patients do not respond to immune checkpoint inhibitor (ICI)-based therapies with CD8+ T cell exhaustion being the main contributing factor. IL-10 has been found to exhibit greater cytotoxicity by directly activating terminally exhausted tumor-infiltrating CD8+ T cells. IL-10 has proven to be relatively safe in Phase I/Phase Ib clinical trials. However, IL-10 can cause severe side effects, such as grade 3-4 hematological toxicity, limiting its development and clinical applications.

Given that, we have developed the IL-10M platform. The activity of IL-10M is reduced through engineering, after which the IL-10M/antibody fusion protein is formulated. The fusion protein is enriched in the tumor microenvironment via the antibody moiety, which reduces toxicity and enhances efficacy. We have developed several fusion proteins with promising pre-clinical anti-tumor efficacy. These engieered molecules include FP008 (IL-10M/anti-PD-1), FPE017 (IL-10M/anti-EGFR), and FPR016 (IL-10M/anti-VEGFR2).

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The bispecific/trispecific TCE platform

The low infiltration of T cells and the suppressive tumor microenvironment significantly inhibit T cell engager's (TCE) therapeutic efficacy in solid tumors. Our trispecific T-cell engager (TCE) platform, utilizing proprietary nanobodies, incorporates second signals to mimic dual-signal T-cell activation. This approach effectively activates T cell proliferation within the tumor microenvironment, addressing T-cell dysfunction or apoptosis that arises from insufficient second signals. The next-generation nanobody-based trispecific TCE can preferentially target CD8+ T cells, inducing stronger cytotoxic activity and lower cytokine toxicity. Our Fibody platform replaces CH1/CL of the antibody moiety with a receptor/ligand to avoid light chain mispairing and enhance the activation mechanism of the T cell's third signals (cytokines). The platform can be used to construct TCEs from IgGs.

VHH constructs the next-generation TCE

We have developed the TCE platform with anti-TCR/CD3 nanobodies, instead of traditional anti-CD3 FAB/scFv, thereby avoiding complex protein engineering.

The next-generation trispecific TCEs, incorporating co-stimulatory signals or exhibiting CD8+ T-cell bias, demonstrate greater efficacy compared to traditional bispecific TCEs.

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●Compared to traditional anti-CD3 FAB/scFv, anti-TCR/CD3 nanobodies are smaller and can avoid light chain mispairing, laying a solid foundation for constructing trispecific TCEs.

●Human/cynomolgus monkey cross-reactivity makes it easier to assess toxicities.

●The second signals of the next-generation trispecific TCEs help better activate T cells, solving the problem of T cell exhaustion when only first signals are present.

●The next-generation trispecific TCEs with CD8+ T cell-bias demonstrate stronger cytotoxicity and lower cytokine risk.

The Fibody bispecific antibody platform

We have leveraged our experiences in developing fusion proteins to design Fibody. The cytokine receptor/ligand pair replaces CH1/CL domain of antibody to avoid light chain mispairing and retain the IgG conformation for greater druggability.

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●Solving light chain mispairing problems

●High expression level (＞4 g/L), high purity (> 95%)

●Retaining IgG conformation

●Incorporating a third functional domain, such as a cytokine, to develop TCEs with better efficacy

●Covering multiple cytokines and their receptors through patented technologies

The PROTiNb (proteolysis targeting intra-nanobody) platform

While similar technologies are at their nascence, ours is at the global forefront, demonstrating substantial potential.

PROTiNb, an innovative targeted protein degradation platform, delivers RNA to cells for expression and efficiently degrades target proteins to achieve therapeutic effects. PROTiNb molecule comprises a nanobody targeting intracellular target, linked to an E3 ligase element.

Leveraging our antibody discovery platform, we can rapidly screen for nanobodies against intracellular targets, including those previously undruggable targets. We have optimized a series of E3 ligases, expanding the options available for degrading targets independent on endogenous E3 ligases. This improves druggability while reducing the impact on the biological function of endogenous E3 ligases. The unique properties and advantages of PROTiNb provide an effective solution for previously undruggable targets and will benefit the patients with different indications.

Advantages of PROTiNb

●By degrading rather than merely surpressing target proteins, PROTiNb is more effective and requires a lower dosage.

●PROTiNb can target undrugable targets through VHH with high specificity and better safety profile.

●Optimized E3 package can apply to combination with antibodies for broad targets.

●Gene-based drugs align with current and future technologies and pharmaceutical forms, including directed evolution, RNA drugs, gene editing, and novel delivery technologies.

Inhibition of cell proliferation in vitro

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●RAS PROTiNb efficiently inhibited tumor cell proliferation in vitro by degrading RAS proteins

●Dox-induced RAS PROTiNb inhibited tumor growth in the in vivo tumor model.

Antibody discovery platform

Mammalian cell display platform

The mammalian cell display platform can be widely used for the development of monoclonal antibodies, bispecific antibodies and fusion proteins.