Updates on the mechanisms of toxicities associated with monoclonal antibodies targeting growth factor signaling and immune cells in cancer

Abstract

Monoclonal antibody (mAb)-based immunotherapy currently is considered to be an optimal therapeutic approach to cancer treatment, either in combination with surgery, radiation, and/or chemotherapy or alone. Various solid tumors and hematological malignancies have been characterized by distinct molecular targets, which could be utilized as innovative anticancer agents. Notably, receptor tyrosine kinases, including HER2, EGFR, VEGFR, and PDGFR, which act as receptors for growth factors, serve as crucial target proteins, expanding their role in the cancer therapeutic market. In contrast to conventional anticancer agents that directly target cancer cells, the advent of immunotherapy introduces novel approaches, such as immune checkpoint blockers (ICBs) and mAbs targeting surface antigens on immune cells in hematological malignancies and lymphomas. While these immunotherapies have mitigated the acquired resistance observed in traditional targeted therapies, they also exhibit diverse toxicities. Herein, this review focuses on describing the well-established toxicities and newly proposed mechanisms of monoclonal antibody toxicity in recent studies. Understanding these molecular mechanisms is indispensable to overcoming the limitations of mAbs-based therapies, facilitating the development of innovative anticancer agents, and uncovering novel indications for cancer treatment in the future.

Keywords: Anticancer agents; Cancer treatment; Immunotherapies; Monoclonal antibody toxicities.

Fig. 1

FDA approved monoclonal antibodies targeting growth factor signaling. (1) HER2-targeted mAbs. HER2 is dimerization partner for HER family member proteins (HER1, HER2, HER3 and HER4) modulating various cellular processes. It is overexpressed in a significant proportion of cancer patients resulting in an increased recurrence and poor prognosis. (2) EGFR-targeted mAbs. EGFR signaling in cancer cells promotes cell proliferation, migration, invasion and survival, and these can be blocked with mAbs against the EGFR. (3) VEGF/VEGFR-targeted mAbs. VEGF initiates a series of steps that constitute the process of sprouting angiogenesis. (4) PDGFR-targeted mAb. Targeting PDGFR using PDGF/PDGFR antibodies could be an potential approach to inhibit the migration and proliferation of cancer cells

Fig. 2

Toxicities of mAbs targeting growth factor signaling. Schematic representation of the four antibodies targeting growth factor signaling

Fig. 3

The characteristics of immune-related adverse effects (irAEs) induced using ICB. (1) Reported deaths resulting from the use of ICB. Anti-CTLA-4 antibodies and anti-PD-1/PD-L1 antibodies display differential toxicities leading to death. (2) Major toxicities arising from the use of ICB manifest at barrier organs. (3) ICB use manifests endocrine toxicities. These distinct toxicities may arise from the expression of CTLA-4 (pituitary glands) and PD-L1 (thyroid). (4) Some irAEs are similar to autoimmune diseases, including IBD, autoimmune thyroid disease, and type 1 diabetes. The therapeutic agents used in autoimmune diseases have been reported to be effective in managing corticosteroid-refractory irAEs

Fig. 4

Toxicities related to antibodies targeting antigens expressed on B lymphocytes. (Left) The representative toxicity of anti-CD20 antibodies is infusion-related reactions arising from cytokine release. The HBV reactivation caused by the use of anti-CD20 antibodies has been reported, but this is still controversial. (Middle) Anti-CD30 antibodies are associated with peripheral neuropathy, but this major toxicity is thought to derive from MMAE attacking the peripheral nerve. (Right) Anti-CD19 antibodies are related to neurological adverse events and cytokine release syndrome due to activated T cells secreting greater amounts of cytokines