Emerging new therapeutic antibody derivatives for cancer treatment

Abstract

Monoclonal antibodies constitute a promising class of targeted anticancer agents that enhance natural immune system functions to suppress cancer cell activity and eliminate cancer cells. The successful application of IgG monoclonal antibodies has inspired the development of various types of therapeutic antibodies, such as antibody fragments, bispecific antibodies, and antibody derivatives (e.g., antibody-drug conjugates and immunocytokines). The miniaturization and multifunctionalization of antibodies are flexible and viable strategies for diagnosing or treating malignant tumors in a complex tumor environment. In this review, we summarize antibodies of various molecular types, antibody applications in cancer therapy, and details of clinical study advances. We also discuss the rationale and mechanism of action of various antibody formats, including antibody-drug conjugates, antibody-oligonucleotide conjugates, bispecific/multispecific antibodies, immunocytokines, antibody fragments, and scaffold proteins. With advances in modern biotechnology, well-designed novel antibodies are finally paving the way for successful treatments of various cancers, including precise tumor immunotherapy, in the clinic.

Fig. 1

Representative therapeutic antibodies and their derivatives. a TCR-mimic antibody; b IgG antibody and antibody fragments; c antibody-drug conjugate (ADC) and its mechanism of action; d multifunctional antibodies, such as bispecific antibodies, immunocytokine (antibody-cytokine fusion protein)

Fig. 2

Schematic representation of the FDA-approved antibody-drug conjugate (ADC)

Fig. 3

Schematic representation of antibody-siRNA conjugates (ARCs). a Antibody siRNA complex is constructed using electrostatic non-covalent interactions. b The THIOMAB-based ARC. The siRNA is chemically conjugated with the introduced cysteine of IgG antibody (THIOMAB, Genentech Inc) via thiol-maleimide reaction to achieve site-specific conjugation. c IgG-based ARC that incorporates cell-penetrating peptide in the linker to facilitate endosomal escape of siRNA. d Fab-based ARC. The siRNA or ASO is chemically conjugated to the C-terminus of Fab

Fig. 4

Schematic overview of the IgG antibody structure and representative multispecific antibody formats at clinical stages. a The classical IgG antibody structure that consists of Fab and Fc regions. The single chain variable fragment (scFv) is a combination of the variable region of heavy chain (VH) and variable region of light chain (VL) domains. b Various multispecific antibody formats that are FDA-approved or under clinical studies. They are classified into the following categories: IgG-like constructs (with Fc region), non-IgG-like fragments (without Fc region). ScFv single-chain variable fragment, DVD-Ig dual-variable-domain immunoglobulin, BiTE bispecific T-cell engager, HLE-BiTE half-life-extended BiTE, TandAb tandem diabody, DART dual-affinity retargeting molecule, CODV cross-over dual variable region, TriKE trispecific NK-cell engager, TriTAC trispecific T-cell activation constructs

Fig. 5

Different antibody or antibody fragment-cytokine fusion proteins. a Cytokine fused to the N-terminus of the Fc domain; b Cytokine fused to the C-terminus of the Fc domain; c Cytokine fused to the C-terminus of the Fab; d Cytokine fused to the C-terminus of the scFv; e ScFv-cytokine-scFv fusion protein; f F(ab')-cytokine fusion protein; g IgG format immunocytokine without CH1 and CL; h Representative IgG format immunocykine-Bintrafusp alfa (M7824). A bifunctional antibody fusion protein composed of anti-PD-L1 human IgG1 and human TGF-βRII extracellular domain as the TGF-β trap, though a flexible glycine-serine linker fused to CH3-C terminus of IgG. Bintrafusp alfa blocks PD1-PDL1 as well as TGFR2-TGFβ signaling pathways to relieve immune suppression and remove the immune inhibition

Fig. 6

Different formats of antibody fragments and their derivatives