Targeting CEA and CD3

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  • Pathways Overview
  • Potential of Combinations
Pathways Overview

Simultaneous binding of CEA on tumour cells and CD3 on T cells activates T cells, resulting in T-cell–mediated tumour killing

CEA: a tumour surface antigen

CEA

Carcinoembryonic antigen (CEA) is a cell surface protein and a member of the immunoglobulin superfamily.1,2

  • Under normal conditions, CEA is expressed at low levels on the apical surface of epithelial cells and may function as an adhesion molecule
  • In cancer, CEA is overexpressed on the cell surface of a variety of tumour types, including colorectal, non-small cell lung, breast, pancreatic, and gastric cancers

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 CEA on tumour cells and CD3 on T cells engages T cells and redirects their activity against tumour cells. T-cell activation—a result of the CEA-CD3 interaction—promotes the proliferation/expansion of pre-existing T cells and the recruitment of new T cells from the peripheral blood to the tumour microenvironment, which may further contribute to antitumour activity.1,2,4

  • In preclinical models, binding of T-cell bispecific antibodies to CEA and CD3 induced significant tumour regression through T-cell proliferation at tumour sites and recruitment of new T cells to the tumour bed
CEA and CD3 interaction

 

 
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Potential of Combinations

CEA CD3 T-cell bispecific antibodies may be used in combination with PD-L1 inhibition to produce enhanced antitumour effects

By redirecting T cells to the tumour microenvironment, a CEA-CD3 T-cell bispecific may restore immune activity in tumour cells.1,5,6 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 tumour cells and T cells.1,2,4,7-9

  • This mechanism, known as adaptive immune resistance, can be overcome by PD-L1 blockade
  • Use of T-cell bispecifics targeting CEA and CD3 in combination with PD-L1-targeted therapy may address adaptive immune resistance mechanisms to enhance antitumour activity

CEA-CD3 binding + PD-L1 inhibition

Roche is actively investigating the potential of targeting CEA and CD3 using the 2:1 TCB platform, alone and in combination with PD-L1 inhibition, for the treatment of CEA-expressing solid tumours, such as colorectal cancer

 
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References 
  1. Bacac M, Klein C, Umana P. CEA TCB: a novel head-to-tail 2:1 T cell bispecific antibody for treatment of CEA-positive solid tumours. Oncoimmunology. 2016;5:e1203498. PMID: 27622073
  2. Bacac M, Fauti T, Sam J, et al. A novel carcinoembryonic antigen T-cell bispecific antibody (CEA TCB) for the treatment of solid tumors. Clin Cancer Res. 2016;22:3286-3297. PMID: 26861458
  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. Lehmann S, Perera R, Grimm HP, et al. In vivo fluorescence imaging of the activity of CEA TCB, a novel T-cell bispecific antibody, reveals highly specific tumor targeting and fast induction of T-cell-mediated tumor killing. Clin Cancer Res. 2016;22:4417-4427. PMID: 27117182
  5. Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;20:838-847. PMID: 25728220
  6. Frankel SR, Baeuerle PA. Targeting T cells to tumour cells using bispecific antibodies. Curr Opin Chem Biol. 2013;17:385-392. PMID: 23623807
  7. 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
  8. 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
  9. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212. PMID: 22236695

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