CD3 BISPECIFICS

Overview

T cell receptors (TCRs) are protein complexes formed by six different polypeptides. The CD3 (cluster of differentiation 3) complex is part of the T-cell receptor (TCR) complex and is composed of two CD3ε, one CD3γ, one CD3δ, and two CD3ζ chains.1,2 CD3 complex ensures signal transduction and plays an important role in T-cell activation.1-3

A bispecific antibody approach may allow for binding to targets on malignant cells, while simultaneously binding to CD3 on T cells, inducing activation and cytotoxic activity of T cells enabling lysis of target-expressing malignant cells.1,5


Diagram of the T-cell receptor (TCR) complex.

CD3 bispecific antibodies (bsAb) induce the activation and cytotoxic activity of effector T cells enabling lysis of target-expressing malignant cells1,3,5.

  • CD3 bsAb activate T cells by binding CD3 on T cells and a tumor-associated antigen (TAA) on the cancer cells. Consequently, all available T cells can bind to target-expressing cells irrespective of the peptide/major histocompatibility complex (MHC) specificity of their T-cell receptor (TCR) 1,3.
  • Activation of the TCR-CD3 complexes leads to the formation of a cytolytic synapse between the T cell and the tumor cell which results in the release of perforin and granzynes and subsequent tumor cell death by apoptosis1.

T-cell redirection with bispecific antibodies in which one binding arm recognizes a tumor antigen and the other binding arm recognizes CD3 on T-cells.


CD3 bsAbs in clinical trials either lack an Fc region or contain an engineered Fc domain to minimize interaction with Fc receptors.1,3

  • The presence of an Fc domain increases the in vivo half-life through binding to the neonatal Fc receptor.3


A key CD3 bsAb development consideration is a need for a format that either significantly limits or eliminates cyokine release syndrome (CRS), since CRS appears to be dose-limiting in most cases for this class of molecules1

IMPLICATIONS IN CANCER

Immunotherapy of cancer with CD3 bsAb is a fast developing field, and multiple TAAs are under evaluation for both hematological and solid tumor malignancies with > 44 different CD3 bs Abs in clinical development.3,5

  • The idea of using the cytotoxic capacity of T cells through CD3-targeting bispecific antibodies (CD3 bsAb) to kill tumor cells dates back to 1980’s.3,6

TUMOR-ASSOCIATED ANTIGEN TARGETS

CD20

CD20 (cluster of differentiation 20) on B-cells is a clinically well-validated target that is expressed in a wide variety of B-cell malignancies with limited normal tissue expression beyond B cells.7,8

Survivin HLA-A2

Survivin, an essential apoptotic-related protein, is an attractive intracellular tumor target expressed in multiple solid and hematological cancers that is readily amenable to TCR-directed therapeutics.4

5T4

5T4 (trophoblast glycoprotein, TPBG) is an oncofetal antigen and overexpression of the 5T4 gene in different cell types is characterized by morphological changes, inhibition of cell-cell interaction, E-cadherin downregulation, cytoskeletal disruption, reduced adherence, and increased motility.9

  • 5T4 expression has also been shown to be associated with cancer stem cell mobilization and metastatic behavior.9

5T4 is a transmembrane tumor antigen expressed in multiple tumors types with limited expression in healthy tissue.10

  1. Strohl WR, Naso M. Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells. Antibodies (Basel). 2019 Jul 3;8(3):41.
  2. Alcover A, et al. Cell Biology of T Cell Receptor Expression and Regulation. Annu. Rev. Immunol. 2018. 36:85–107.
  3. Benonisson H, et al. CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory. Mol Cancer Ther. 2019;18(2):312-322.
  4. Reilly EB, et al. ABBV-184: A novel survivin specific T cell receptor/CD3 bispecific therapeutic that targets both solid tumor and hematological malignancies. Abstract #DDT03-01. AACR Virtual Annual Meeting 2020.
  5. Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019 Aug;18(8):585-608.
  6. Staerz UD, Kanagawa O, Bevan MJ. Hybrid antibodies can target sites for attack by T cells. Nature. 1985 Apr 18-24;314(6012):628-31.
  7. Hutchings M, et al. Epcoritamab (GEN3013; DuoBody-CD3×CD20) to induce complete response in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: Complete dose escalation data and efficacy results from a phase I/II trial. Poster #8009. 56th Annual ASCO Meeting and Exposition; May 2020
  8. Engelberts PJ, et al. DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing. EBioMedicine. 2020 Feb;52:102625.
  9. Harrop R, et al. Cancer stem cell mobilization and therapeutic targeting of the 5T4 oncofetal antigen. Ther Adv Vaccines Immunother. 2019;7: 1–17.
  10. Xu Y, et al. Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma. Cancer Immunol Immunother. 2019 Dec;68(12):1979-1993.

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