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T cell bispecific antibodies (TCBs) are potent molecules that upon simultaneous binding
to tumour cells and T cells trigger strong T cell activation resulting in the killing
of tumour cells. CEA TCB (RG7813) is a novel bispecific antibody targeting carcinoembryonic
antigen (CEA), often overexpressed on solid tumours (e.g. colorectal, gastric, pancreatic,
lung carcinoma etc.), and the CD3 epsilon chain present on T cells.
CEA TCB bears several innovative technological features that distinguish it from other
bispecific antibodies currently in (pre-)clinical development: (a) bivalency for tumour
antigen translating into higher avidity, superior potency and better differentiation
between high and low antigen-expressing cells; (b) head-to-tail fusion geometry for
anti-tumour and CD3-binding domains, resulting in higher potency compared to conventional
IgG-based TCBs; (c) extended half-life compared to non-Fc-based TCBs; (d) fully silent
Fc ensuring lower risk of FcgR-mediated infusion reactions; and (e) robust production
using standard manufacturing processes (enabled by “CrossMAb” and knob-into-hole bispecific
antibody technologies).
In vitro, CEA TCB mediates potent target-dependent T cell cytotoxicity, T cell activation,
proliferation, and cytokine release in killing assays, exclusively in the presence
of CEA-expressing target-cells. CEA TCB activity correlates with CEA expression level,
showing higher potency against tumour cells with high expression of CEA. In vivo, CEA TCB induces dose- and time-dependent regression of CEA-expressing tumours with
variable amounts of immune cell infiltrate. In fully humanised NOG mice, CEA TCB is
efficacious in poorly-infiltrated tumours and converts non-inflamed into highly-inflamed
tumours. Histological and FACS analyses revealed that CEA TCB recruits new T cells
into tumours and/or expands pre-existing ones and is able to induce T cell re-localisation
from the tumour periphery into the tumour bed. Surprisingly, CEA TCB treatment also
qualitatively alters the composition of intratumoural T cells resulting in an increased
frequency of activated (CD69, CD25), proliferating (Ki67) and differentiated T cells
(having effector memory phenotype) that are ready to kill (express high levels of
Granzyme B).
Taken together, these preclinical data show that CEA TCB is a novel tumour-targeted
T cell bispecific antibody with promising anti-tumour activity and the novel ability
to modify the tumour microenvironment. Phase 1 clinical trials with CEA TCB are currently
ongoing. Future studies will focus on identification of combination partners that
inhibit T cell suppression and unleash the full potential of T cell activity.
Presented in Plenary Session 4 : Immunomodulatory agents.
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