Application and future prospects of bispecific antibodies in the treatment of non-small cell lung cancer

Abstract

As the leading cause of cancer-related deaths, lung cancer remains a noteworthy threat to human health. Although immunotherapies, such as immune checkpoint inhibitors (ICIs), have significantly increased the efficacy of lung cancer treatment, a significant percentage of patients are not sensitive to immunotherapies and patients who initially respond to treatment can quickly develop acquired drug resistance. Bispecific antibodies (bsAbs) bind two different antigens or epitopes simultaneously and have been shown to enhance antitumor efficacy with suitable safety profiles, thus attracting increasing attention as novel antitumor therapies. At present, in addition to the approved bsAb, amivantamab, three novel bsAbs (KN046, AK112, and SHR-1701) are being evaluated in phase 3 clinical trials and many bsAbs are being evaluated in phase 1/2 clinical trials for patients with non-small cell lung cancer (NSCLC). Herein we present the structure, classification, and mechanism of action underlying bsAbs in NSCLC and introduce related clinical trials. Finally, we discuss challenges, potential solutions, and future prospects in the context of cancer treatment with bsAbs.

Keywords: Bispecific antibody; challenges; non-small cell lung cancer; novel antitumor therapy; structure.

Figure 1

The evolutionary history map of the bsAbs. IgG subtype bispecific antibodies are placed above the timeline and the non-IgG subtype bispecific antibodies are placed below the timeline. Abs, antibodies; ART-Ig, asymmetric reengineering technology immunoglobulin; bsAb, bispecific antibody; BiTE, bispecific T-cell engager; CrossMab, cross-specific monoclonal antibody; DVD-Ig, dual variable domain-immunoglobulin; DART, dual-affinity re-targeting proteins; EGFR, epidermal growth factor receptor; Fab, fragment antigen-binding; Fc, fragment crystallizable; IgG, immunoglobulin G; ImmTAC, immune-mobilizing monoclonal T-cell receptors against cancer; NSCLC, non-small cell lung cancer; scFv, single-chain fragment variable; TandAb, tandem diabody; TKI, tyrosine kinase inhibitor; XmAb, xencor monoclonal antibody.

Figure 2

Three strategies for bsAb construction. (A) Fusing two hybridoma cells to construct bsAbs. Hybridoma cell A expressing mAb A and hybridoma cell B expressing mAb B are fused to generate a quadroma cell which expresses bsAbs. (B) Constructing bsAbs by chemical conjugation. Two mAbs were digested with enzymes to obtain antibody fragments. The fragments from mAb A and mAb B were then reassociated using chemical crosslinkers to construct bsAbs. (C) Constructing bsAbs by genetic engineering. Through genetic engineering technologies, fragments from two distinct mAbs are randomly recombined to construct bsAb in different platforms. The most common genetic engineering technologies used to construct bsAbs are gene recombination and protein engineering. BsAbs can be divided into three types: symmetric IgG subtype; asymmetric IgG subtype; and non-IgG subtype. ART-Ig, asymmetric reengineering technology immunoglobulin; bsAb, bispecific antibody; BiTE, bispecific T-cell engager; CrossMab, cross-specific monoclonal antibody; DVD-Ig, dual variable domain-immunoglobulin; DART, dual-affinity re-targeting proteins; Fab, fragment antigen-binding; Fc, fragment crystallizable; IgG, immunoglobulin G; ImmTAC, immune-mobilizing monoclonal T-cell receptors against cancer; scFv, single-chain fragment variable; TandAb, tandem diabody; TriKE, TriToxin-targeted killer engager; XmAb, xencor monoclonal antibody.

Figure 3

The framework of this review. CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; c-MET, cellular-mesenchymal epithelial transition; CEA, carcinoembryonic antigen; EpCAM, epithelial cell adhesion molecule; EGFR, epidermal growth factor receptor; FRα, folate receptor alpha; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; LAG-3, lymphocyte activation gene 3; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; TIM-3, T-cell immunoglobulin and mucin domain-containing protein 3; TGF-β, transforming growth factor β; TRPV6, transient receptor potential vanilloid 6; VEGF, vascular endothelial growth factor.

Figure 4

Mechanisms of action underlying bsAbs for the treatment of NSCLC. (A) Bridging two immune modulators to recover T-cell activity. After binding to two immune modulators on the T cell surface, bsAbs can restore the activity of exhausted T cells to initiate a tumor-killing immune response. (B) Redirecting T cell to tumor cell. BsAbs can bind the CD3 on the T cell surface and TAA on the tumor cell surface to redirect T cell. Then, T cells will release perforin and granzyme to kill tumor cells. (C) Inhibiting two signaling pathways. The survival of tumor cells relies on multiple signaling pathways. By targeting two receptors on the surface of tumor cells that are integral to these pathways, bsAbs can inhibit downstream signaling, thereby inducing tumor cell death. (D) bsADC with cytotoxic payload. After linking to tumor cells, bsADC release cytotoxic payload to kill tumor cells. bsADC, bispecific antibody-drug conjugate; CD3, cluster of differentiation 3; bsAb, bispecific antibody; TAA, tumor-associated antigen.