Recent advances in tumor associated carbohydrate antigen based chimeric antigen receptor T cells and bispecific antibodies for anti-cancer immunotherapy

Abstract

Tumor associated carbohydrate antigens (TACAs) are a class of attractive antigens for the development of anti-cancer immunotherapy. Besides monoclonal antibodies and vaccines, chimeric antigen receptor (CAR) T cells and bispecific antibodies (BsAbs) targeting TACA are exciting directions to harness the power of the immune system to fight cancer. In this review, we focus on two TACAs, i.e., the GD2 ganglioside and the mucin-1 (MUC1) protein. The latest advances in CAR T cells and bispecific antibodies targeting these two antigens are presented. The roles of co-stimulatory molecules, structures of the sequences for antigen binding, methods for CAR and antibody construction, as well as strategies to enhance solid tumor penetration and reduce T cell exhaustion and death are discussed. Furthermore, approaches to reduce "on target, off tumor" side effects are introduced. With further development, CAR T cells and BsAbs targeting GD2 and MUC1 can become powerful agents to effectively treat solid tumor.

Keywords: Bispecific antibody; CAR T cell; Cancer; GD2 ganglioside; Immunotherapy; Mucin-1.

Figure 1.

Structure of the GD2 ganglioside.

Figure 2.

Schematic demonstration of various GD2 CAR constructs. a) The CAR includes the hinge region as well as the Fc domain (CH2 and CH3); b) CAR without the Fc domain; c) CAR with the hinge attached to the stalk of CD8a; and d) CAR with CD8a stalk only without the hinge region. (Image adapted from [38])

Figure 3.

Construction of UniCAR and TM. A) UniCAR cells do not recognize tumor cells in the absence of TM due to the lack of receptor on T cells towards tumor antigens. B) Upon addition of the TM comprised of the conjugate of anti-GD2 scFv and E5B9, the UniCAR can bind with the TM through E5B9, thus gaining the abilities to recognize GD2⁺ tumor cells.

Figure 4.

Schematic demonstration of MUC1 glycoprotein structure. MUC1 is composed of a heterodimer of MUC1-N linked non-covalently with the transmembrane MUC1-C. MUC1-N contains a variable number of 20 amino acid VNTRs that are heavily glycosylated on serine or threonine residues of each VNTR in normal cells shielding the protein backbone for immune recognition. However, tumor associated MUC1 are hypoglycosylated exposing the protein backbone.

Figure 5.

Schematic representation of various BsAb formats. a) IgG-like BsAbs: i) and ii) IgG-scFv, iii) triomab, iv) quadroma, and v) half molecule exchange format. And b) non-IgG-like BsAb: i) tandem scFv, ii) dual-affinity re-targeting antibody, iii) bi-nanobody, iv) scFv-human serum albumin-scFv.

Figure 6.

Schematic demonstration of the Hu3F8-BsAb structure.

Figure 7.

scFv-based bispecific antibody format of Hu3F8-scBA (V_H is the heavy chain of the variable region, and the V_L is the light chain of the variable region).