Bispecific Antibodies Targeting CD3 and PMEL

Introduction of CD3

CD3 is a complex of four distinct chains (γ, δ, ε, and ζ) that associate with the T cell receptor (TCR) and mediate T cell activation and signaling. CD3 is expressed on the surface of all T cells, regardless of their antigen specificity, and is encoded by genes located on chromosome 11 in humans. CD3 plays a crucial role in T cell development, differentiation, and function, as well as in various immune disorders such as autoimmune diseases, immunodeficiencies, and cancers. CD3 is a well-established target for bispecific antibodies (BsAbs) that aim to redirect T cells to tumor cells expressing a specific antigen, thereby inducing cytotoxicity and cytokine release.

Introduction of PMEL

PMEL is a type I transmembrane glycoprotein that is involved in melanosome biogenesis and pigmentation. PMEL is also known as SILV, gp100, or Pmel17, and is encoded by the PMEL gene located on chromosome 12 in humans. PMEL plays a key role in melanocyte differentiation, melanin synthesis, and melanoma progression, as well as in its immunogenicity and antigenicity in melanoma patients. PMEL is a promising target for bispecific antibodies (BsAbs) that aim to enhance the recognition and elimination of melanoma cells by T cells, especially in combination with other immunomodulatory agents.

Signaling Pathways Involved in Bispecific Antibodies Targeting CD3 and PMEL

The general mechanism of action of BsAbs targeting CD3 and PMEL involves the simultaneous binding of one arm to CD3 on T cells and the other arm to PMEL on melanoma cells, resulting in the formation of an immunological synapse and the activation of TCR signaling pathways. The main signaling pathways that are triggered by BsAbs targeting CD3 and PMEL include the MAPK/ERK, PI3K/AKT, NF-κB, and JAK/STAT pathways, which regulate various aspects of T cell function, such as proliferation, survival, differentiation, effector activity, and memory formation. These signaling pathways can modulate the anti-tumor efficacy and toxicity of BsAbs targeting CD3 and PMEL, as well as the potential strategies to optimize their therapeutic outcomes, such as using different formats, dosages, schedules, or combinations of BsAbs.

Clinic Status of Bispecific Antibodies Targeting CD3 and PMEL

Currently, the FDA has approved only one BsAb targeting CD3 and PMEL, tebentafusp (Immunocore's Kimmtrak®). This soluble TCR-based bispecific molecule received accelerated approval in May 2021 for treating patients with unresectable or metastatic uveal melanoma. Tebentafusp demonstrated significant overall survival improvement in a phase III trial (IMCgp100-202) compared to investigator's choice of therapy. Previous phase I and II trials (IMCgp100-101 and IMCgp100-102) also confirmed favorable safety, pharmacokinetics, pharmacodynamics, and biomarker profiles. Tebentafusp's mechanisms of action involve activating both CD8+ and CD4+ T cells, inducing a pro-inflammatory cytokine milieu, modulating the tumor microenvironment, and generating T cell memory.

Fig.1 Schematic demonstrating the mechanism of action of tebentafusp (Howlett S, 2023)

Table 1. Summary of Tebentafusp

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