Mechanisms of Action and Limitations of Monoclonal Antibodies and Single Chain Fragment Variable (scFv) in the Treatment of Cancer

Abstract

Monoclonal antibodies are among the most effective tools for detecting tumor-associated antigens. The U.S. Food and Drug Administration (FDA) has approved more than 36 therapeutic antibodies for developing novel alternative therapies that have significant success rates in fighting cancer. However, some functional limitations have been described, such as their access to solid tumors and low interaction with the immune system. Single-chain variable fragments (scFv) are versatile and easy to produce, and being an attractive tool for use in immunotherapy models. The small size of scFv can be advantageous for treatment due to its short half-life and other characteristics related to the structural and functional aspects of the antibodies. Therefore, the main objective of this review was to describe the current situation regarding the mechanisms of action, applications, and limitations of monoclonal antibodies and scFv in the treatment of cancer.

Keywords: cancer; mechanism of action; monoclonal antibodies; scFv; treatment.

Figure 1

Effector mechanisms of therapeutic mAbs in cancer therapy. (A) Signaling pathway blocking. (B) Antibody-dependent cellular cytotoxicity. (C) Complement-dependent cytotoxicity. (D) Antibody-dependent cellular phagocytosis. AKT: Protein kinase B, ERK: extracellular signal-regulated kinase, C1q: complement component 1q, MAC: Membrane attack complex, FcγRIII: Fc-gamma receptor III, FcγRI: Fc-gamma receptor I. Image created in BioRender (www.biorender.com, accessed on 20 January 2023).

Figure 2

Mechanism of action of the ADC Tisotumab vedotin-tftv. Tisotumab vedotin-tftv targets and blocks TF, which later is internalized and enters the lysosome-mediated intracellular trafficking. Then, it is enzymatically degraded for the intracellular release of MMAE, which promotes cellular death by microtubule disruption. In addition, releasing MMAE into the tumoral microenvironment promotes the apoptosis of neighboring cancer cells. Red symbol represents the drug released. Image created in BioRender (www.biorender.com, accessed on 20 January 2023).

Figure 3

Structure of scFv. scFv structure is composed of the VH and VL chains of the complete antibody; both segments are linked with a flexible linker for the conservation of the antigen-binding site. Image created in BioRender (www.biorender.com, accessed on 20 January 2023).

Figure 4

Structure and mechanisms of action of scFv approved by the FDA. (A) Blinatumomab structure and mechanism of action. It is composed of variable fragments of bivalent bispecific antibodies linked together. Blinatumomab stimulates a synapse between the CD3+ T cell and the CD19+ tumoral target cells, promoting the upregulation of adhesion molecules, production of cytolytic proteins, and the release of pro-inflammatory cytokines that conveyed to cellular lysis and apoptosis of the CD19+ cells. (B) Moxetumomab pasudotox structure and mechanism of action. It involves an anti-CD22 scFv linked to Pseudomonas exotoxin A PE38 by a peptide bond to VH. Moxetumomab binds to CD22 overexpressed in malignant B cells; later, the complex Moxetumomab-CD22 is internalized by endocytosis. Finally, PE38 catalyzes the ADP-ribosylation of the diphthamide residue in EF-2, which promotes a reduction in the levels of the antiapoptotic protein Mcl-1 and increases the apoptotic rate. Image created in BioRender (www.biorender.com, accessed on 20 January 2023).

Figure 5

Mechanisms of action of scFv in cancer therapy. (A) Chimeric antigen receptor (CAR) T-cells. (B) Nanoparticle-conjugate scFv. (C) Biological activity blocking. IL-2: Interleukin 2, IFN γ: Gamma Interferon, TNF-α: Tumor Necrosis Factor Alpha.

Figure 6

In situ delivering of scFv to tumor sites by vectors. (A) In situ delivery and production system of Trastuzumab scFv by Gene-Engineered Bifidobacterium. Bifidobacterium, a strict anaerobic bacterium, explicitly targets the hypoxic environment of tumors, being a transformed bacterium that expresses anti-HER2 scFv, and this antibody blocks the HER2-mediated signaling pathways. (B) The administration system of an anti-p21Ras scFv by transfected CIK cells. Recombinant adenoviruses loaded with the anti-p21Ras scFv gene can enter CIK cells, replicate, and intracellularly express anti-p21Ras scFv.