Antibody-Based Targeted Interventions for the Diagnosis and Treatment of Skin Cancers

Abstract

Background: Cutaneous malignancies most commonly arise from skin epidermal cells. These cancers may rapidly progress from benign to a metastatic phase. Surgical resection represents the gold standard therapeutic treatment of non-metastatic skin cancer while chemo- and/or radiotherapy are often used against metastatic tumors. However, these therapeutic treatments are limited by the development of resistance and toxic side effects, resulting from passive accumulation of cytotoxic drugs within healthy cells. Objective: This review aims to elucidate how the use of monoclonal antibodies (mAbs) targeting specific tumor associated antigens (TAAs) are paving the way to improved treatment. These mAbs are used as therapeutic or diagnostic carriers that can specifically deliver cytotoxic molecules, fluorophores or radiolabels to cancer cells that overexpress specific target antigens. Results: mAbs raised against TAAs are widely in use for e.g. differential diagnosis, prognosis and therapy of skin cancers. Antibody drug conjugates (ADCs) particularly show remarkable potential. The safest ADCs reported to date use non-toxic photo-activatable photosensitizers (PS), allowing targeted photodynamic therapy (PDT) resulting in targeted delivery of PS into cancer cells and selective killing after light activation without harming the normal cell population. The use of near infrared emitting photosensitizers enables both diagnostic and therapeutic applications upon light activation at the specific wavelengths. Conclusion: Antibody based approaches are presenting an array of opportunities to complement and improve current methods employed for skin cancer diagnosis and treatment.

Insight into the Prospects for Tumor Therapy Based on Photodynamic Immunotherapy

“…This coordinated release allows the induction of a more robust antitumor-immune response with the establishment of immunological memory [91]. NIR light was able to kill tumor cells by binding single antibody conjugates of NIR activatable dyes (trastuzumab and panitumumab) to the membrane, whereas non-cell surface-bound conjugates had no effect [92].…”

Click Chemistry-Generated Auristatin F–Linker–Benzylguanine for a SNAP-Tag-Based Recombinant Antibody–Drug Conjugate Demonstrating Selective Cytotoxicity toward EGFR-Overexpressing Tumor Cells

“…The epidermal growth factor receptor (EGFR) is a member of the transmembrane tyrosine kinase receptor family (HER), comprising an extracellular ligand binding domain (EC), a transmembrane domain (TM), and an intracellular domain with tyrosine function. , EGFR activation starts with ligand binding that triggers dimerization (homo- and/or heterodimerization), which leads to tyrosine kinase domain autophosphorylation. In turn, this activates a cascade of downstream signaling pathways such as the RAS/MAPK, PI3K/Akt, Jak/Stat, and activator-of-transcription 3 (STAT3) pathway, all of which are implicated in the transcriptional regulation of genes involved in cell proliferation, cell survival, migration, and drug resistance. − As a result, novel therapeutic strategies in the form of anti-EGFR monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) (e.g., gefitinib and erlotinib) have been developed. − These therapies work respectively by obstructing EGFR binding with agnostic ligands (mAbs) and by suppressing the intracellular tyrosinase activity through disruption of adenosine-5′-triphosphate (ATP) binding (TKIs). − The clinical success of these therapies was demonstrated by the FDA approval of erlotinib (2004) and gefitinib (2015) for the treatment of non-small-cell lung cancer (NSCLC), and cetuximab (approved in 2004) and panitumumab (2006) mAbs for treating colorectal cancer. ,,, However, these (cetuximab and panitumumab) are yet to demonstrate palpable therapeutic benefits, as they only achieve significant therapeutic efficacies when combined with systemic chemotherapy or radiotherapy and TKIs but not when used as monotherapy. − Therefore, efforts to mitigate these suboptimal therapeutic effects have paved the way for the development of antibody–drug conjugates (ADCs), a fast-growing type of biotherapeutic with the potential to increase the antitumor activity of an antibody. ,− These ADCs typically comprise a mAb serving as a vehicle that selectively recognizes cancer cells overexpressing cognate cell surface receptors in comparison to normal cells. Upon recognition through ligand–receptor binding, the mAb enters the cell to specifically deliver the cytotoxic molecule, which subsequently induces cell death in cancer cells but not in normal cells. ,− …”

“… 4 , 5 , 7 , 8 However, these (cetuximab and panitumumab) are yet to demonstrate palpable therapeutic benefits, as they only achieve significant therapeutic efficacies when combined with systemic chemotherapy or radiotherapy and TKIs but not when used as monotherapy. 7 − 10 Therefore, efforts to mitigate these suboptimal therapeutic effects have paved the way for the development of antibody–drug conjugates (ADCs), a fast-growing type of biotherapeutic 9 with the potential to increase the antitumor activity of an antibody. 1 , 9 − 14 These ADCs typically comprise a mAb serving as a vehicle that selectively recognizes cancer cells overexpressing cognate cell surface receptors in comparison to normal cells.…”