Development of TIM-3-based Bispecific ADCs

As a novel targeted therapy for cancers, bispecific antibody-drug conjugates (ADCs) are displaying great potential and promising. Serval bispecific ADCs against different targets are developed actively in recent years, which need high-quality material such as bispecific antibody and linker-payload. Creative Biolabs is a leader in the field of antibody production and bio-conjugation for more than ten years, we offer a full range of bispecific ADCs design and construction services, from materials preparation to final product characterization.

The Overview of TIM-3

T cell immunoglobulin mucin-(TIM)-3 was identified as a molecule specifically expressed on IFN-γ-secreting CD4+ T helper 1 (Th1) and CD8+ T cytotoxic (Tc1) cells in both mice and humans. The specific expression of TIM-3 on Th1 cells catalyzed investigation into its potential role as a regulator of Th1 cells. TIM-3 acts as a negative regulator of Th1/Tc1 cell function by triggering cell death upon interaction with its ligand, galectin-9. Indeed, targeting the Tim-3 pathway has shown very promising results in human diseases.

Human TIM-3 is a 302 amino acid (aa) type I transmembrane glycoprotein that contains a membrane distal immunoglobulin variable (IgV) domain and a membrane proximal mucin domain. TIM-3 belongs to the immunoglobulin superfamily (IgSF) and recent studies have revealed the 3D structure of the IgV domain of TIM-3.TIM-3 IgV domains consist of two anti-parallel β sheets that are tethered by a disulfide bond. Additional two disulfide bonds are formed by four noncanonical cysteines that are invariant within TIM proteins and unique among IgSF members. They stabilize the IgV domain of TIM-3 and reorient the CC’ loop so that it is close to the FG loop, resulting in the formation of a “cleft” or “pocket” structure in TIM-3 as well as other TIM proteins. This unique cleft structure is not found in other IgSF proteins and has been predicted to be involved in ligand binding.

Fig.1 Models for TIM-3-ligand interactions. (Wolf, 2020)

Antibodies-based Therapeutics Targeting TIM-3

Immune cells that express TIM-3 promote immune tolerance to tumors and thus therapeutic antibodies that target TIM-3 have been developed and tested for various cancer therapy. Studies in multiple animal models have shown that antibody-mediated TIM-3 inhibition enhances the activity of immune checkpoint blockade. Combining anti-TIM-3 with anti-PD-1 therapy might be a viable option to overcome T-cell exhaustion in patients and promote responses to immune checkpoint blockade. In addition, antibodies against TIM-3 are being investigated in multiple clinical trials.

NCT03680508 is a phase II trial, testing anti-TIM-3 mAb TSR-022 in combination with anti-PD-1 mAb TSR-042 in patients with hepatocellular carcinoma. Early data suggests that blocking TIM-3 enhances cytotoxic T-cell-mediated tumor lysis.

Patent EP3356411A1 describes a method by producing anti-TIM3/anti-PD-1 bispecific antibodies and their potential in cancer treatment. These data are in line with data in preclinical models showing the superior efficacy of TIM3 pathway and PD1 pathway co- blockade over single- agent treatments.

RO7121661 is a bispecific antibody targeting PD-1 and TIM-3 simultaneously. It was developed by Roche and a phase I dose-escalation and expansion study has been ongoing on advanced solid tumors.

What Can We Do for You?

With years of experience and plenty of researches, scientists from Creative Biolabs have investigated and established a series of approaches for bispecific ADC production. We have constructed different epitope combinations for TIM-3-based bispecific ADCs development, such as TIM-3 x PD-1 and TIM-3 x LAG-3. If you are interested in our services, please contact us for more details.

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