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Review
. 2020 May 7:11:762.
doi: 10.3389/fimmu.2020.00762. eCollection 2020.

Bispecific, T-Cell-Recruiting Antibodies in B-Cell Malignancies

Margaux Lejeune  1 , Murat Cem Köse  1 , Elodie Duray  1 , Hermann Einsele  2 , Yves Beguin  1   3 , Jo Caers  1   3
Affiliations
Review

Bispecific, T-Cell-Recruiting Antibodies in B-Cell Malignancies

Margaux Lejeune et al. Front Immunol. .

Abstract

Bispecific antibodies (BsAbs) are designed to recognize and bind to two different antigens or epitopes. In the last few decades, BsAbs have been developed within the context of cancer therapies and in particular for the treatment of hematologic B-cell malignancies. To date, more than one hundred different BsAb formats exist, including bispecific T-cell engagers (BiTEs), and new constructs are constantly emerging. Advances in protein engineering have enabled the creation of BsAbs with specific mechanisms of action and clinical applications. Moreover, a better understanding of resistance and evasion mechanisms, as well as advances in the protein engineering and in immunology, will help generating a greater variety of BsAbs to treat various cancer types. This review focuses on T-cell-engaging BsAbs and more precisely on the various BsAb formats currently being studied in the context of B-cell malignancies, on ongoing clinical trials and on the clinical concerns to be taken into account in the development of new BsAbs.

Keywords: BiTE; bispecific T-cell engager; bispecific antibodies; clinical development; concerns; leukemia; lymphoma; myeloma.

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Figures

FIGURE 1
FIGURE 1
BsAb formats studied for hematological B-cell malignancies (A), BiTE (Tandem scFvs); (B) DART; (C) TandAb (Tandem diabodies); (D) BAT; (E) TDB: Xmab (scFv-Fab IgG); (F) TCB: CrossMAb; (G) TDB: DuoBody; (H) TriFAb (Rat-mouse hybrid IgG). The different antibody domains are as follows: green, variable region of heavy chain 1 (VH 1); red, variable region of heavy chain 2 (VH 2); yellow, variable region of light chain 1 (VL 1); pink, variable region of light chain 2 (VL 2); light purple, constant region of light rat chain; dark purple, heavy chain of immunoglobulin G2b (IgG2b); light blue and light gray, constant regions of light mouse chain; dark blue and dark gray, heavy chains of mouse IgG2b; turquoise circles, Knob-in-Hole (KiH) BiTE, bispecific T-cell engager; DART, dual-affinity re-targeting; Fab, Fab region; S, disulfure; scFv, single-chain variable fragment; TandAb, tandem diabody; TDB, T-cell-dependent bispecific antibody; TriFAb, trifunctional antibody, triomab.
FIGURE 2
FIGURE 2
B-cell subtypes and associated malignancies. From Hematopoietic stem cell differentiation into myeloid and lymphoid lineages. After Ag-binding, B-lymphocytes further mature in lymphoid tissues where they undergo various morphological, genetic, and chromosomal alterations. As a consequence, various cell surface Ags reside on cell membrane along maturation process. Disruptions in these mechanisms may lead to the development of malignancies. The B-cell malignancies are divided into subgroups based on location, subtype and activation state of B-cells. This figure is adapted from (70, 159).
FIGURE 3
FIGURE 3
Antigen expression during B-cell maturation. Cell surface Ags and their presence at in different B-cell subtypes. This figure is adapted from (160).
See this image and copyright information in PMC

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