Targeting CD20 and CD3

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  • Pathways Overview
  • Potential of Combinations
Pathways Overview

Simultaneous binding of CD20 on B cells and CD3 on T cells results in T-cell activation and malignant B-cell killing

CD20: a B-cell surface antigen

CD20

CD20 is a transmembrane protein and B-cell surface marker that is involved in the development and differentiation of B cells.1,2

  • C20 is expressed in a majority of B-cell malignancies, including chronic lymphocytic leukaemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma

CD3: a T-cell activator

CD3

CD3 is a multimeric protein composed of 4 subunits (γ, δ, ε, ζ), which are part of the T-cell receptor (TCR) complex on the surface of T cells.3

  • When crosslinked, the TCR induces downstream signalling events that result in T-cell activation

Binding of a T-cell bispecific antibody to CD20 on malignant B cells and CD3 on T cells engages T cells and redirects their activity against B cells. T-cell activation—a result of the CD20-CD3 interaction—promotes the proliferation/expansion of pre-existing T cells, which may further contribute to the depletion of malignant B cells.4,5

  • In a variety of preclinical models, binding of T-cell bispecific antibodies to CD20 and CD3 resulted in potent B cell killing
CD20 and CD3 interaction
 
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Potential of Combinations

CD20 CD3 bispecific antibodies may be used in combination with PD-L1 inhibition to produce enhanced anticancer effects

By redirecting T cells, CD20-CD3 bispecific antibodies may restore immune activity against malignant B cells. However, this interaction induces T-cell activation with subsequent IFN-γ release, which has been demonstrated to promote upregulation of PD-L1, a negative immune regulator, on the surface of B cells and T cells.4,5,7

  • This mechanism, known as adaptive immune resistance, can be overcome by PD-L1 blockade
  • Use of bispecific antibodies targeting CD20 and CD3 in combination with PD-L1 inhibition may address adaptive immune resistance mechanisms to enhance anticancer activity against various B-cell malignancies
CD20

Roche is actively investigating the potential of targeting CD20 and CD3 with both the 2:1 TCB or 1:1 TDB platform, and in combination with PD-L1 inhibition, for the treatment of B cell malignancies

 
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References 
  1. Naeim F, Rao PN, Song SX, Grody WW. Principles of immunophenotyping. In Atlas of Hematopathology. 2013;25-46.
  2. Prevodnik VK, Lavrenčak J, Horvat M, Novakovič BJ. The predictive significance of CD20 expression in B-cell lymphomas. Diagn Pathol. 2011;6:33. PMID: 21486448
  3. Borroto A, Arellano I, Blanco R, et al. Relevance of Nck-CD3 epsilon interaction for T cell activation in vivo. J Immunol. 2014;192:2042-2053. PMID: 24470497
  4. Sun LL, Ellerman D, Mathieu M, et al. Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies. Sci Transl Med. 2015;7:287ra70. doi:10.1126/scitranslmed.aaa4802. PMID: 25972002
  5. Sun LL, Wang P, Clark R, et al. Preclinical characterization of combinability and potential synergy of anti-CD20/CD3 T-cell dependent bispecific antibody with chemotherapy and PD-1/PD-L1 blockade. Blood. 2016;128:4168.
  6. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568-571. PMID: 25428505
  7. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27:1492-1504. PMID: 27207108

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