MUC1 Antibody-Based Therapeutics: The Promise of Cancer Immunotherapy

Abstract

Antibody-based targeted therapies have been able to target cancers with enhanced specificity and high efficacy. In this regard, identifying cancer markers (antigens) that are only present (tumor-specific antigens) or have an increased expression (tumor-associated antigen) on the surface of cancer cells is a crucial step for targeted cancer treatment. Various cancer antigens have already been used for therapeutic and diagnostic purposes. MUC1 is one of the most important tumor markers with high levels of expression in various solid tumors which makes it as a potential target for antibody-based therapies. This review discusses preclinical and clinical results from various platforms based on monoclonal antibodies, nanobodies as well as bispecific antibodies against MUC1. We also highlight unmet challenges that must be overcome to generate more effective cancer immunotherapy strategies.

MUC1: Structure, Function, and Clinic Application in Epithelial Cancers

“…Despite these advances, the detailed mechanisms by which MUC1 exerts its effects remain to be explored. Even though MUC1 vaccines and antibodies are being developed, with some having shown significant therapeutic effects and currently undergoing phase I/II clinical trials, certain side-effects and clinical safety issues need to be further explored and confirmed [ 3 , 109 , 110 ]. In conclusion, MUC1 is inextricably linked to various epithelial cancers, mandating further explorations of this phenomenon.…”

MUC1-Targeted Radiopharmaceuticals in Cancer Imaging and Therapy

“…111 GGSK-1/30 is an anti-MUC1 IgG1 that exclusively targets tumor-associated MUC1 in the absence of any binding to fully glycosylated huMUC1 expressed on healthy epithelial cells. 65 It is demonstrated that GGSK-1/30 binds to breast cancer cells more strongly than commercially available mAbs SM3 and HMFG1. Recently, the exceptional specificity of GGSK-1/30 for hu(TA)MUC1 has allowed for the generation of an innovative diagnostic probe for the detection of hu(TA)MUC1 expressing breast tumors by conjugating this Ab with radioisotope 89 Zr.…”

“…C595 (also known as NCRC48) is a murine IgG3 antibody that has been found to target MUC1 by binding to the RPAP motif within the protein core. 65 Radiolabeled conjugates of C595 have been applied for the diagnosis and therapy of MUC1-positive tumors. 76 In a clinical study by Kunkler et al 111 In-labeled Ab C595 was used for the immunoscintigraphy of patients with bladder tumors.…”

“…112 TAB004 is a murine IgG1 mAb initially developed by immunizing Balb/c mice with lysates from MUC1-expressing tumors that are developed in a human tMUC1-bearing transgenic mouse, and it identifies the STAPPVHNV sequence within the TR sequence of hypoglycosylated TA-MUC1. 65 In 2020, Kelly et al used a humanized form of TAB004 (hTAB004) conjugated with a chelator (DOTA) to allow radiolabeling with indium-111 and actinium-225 while achieving high radiolabeling efficiency, purity, and stability. In vivo studies of 111 In-DOTA-hTAB004 in mice bearing orthotopic HCC70 tumors demonstrated a high tumor targeting increase over time (65.4 ± 15.2%ID/g at 120 h) with the tumor having 12.7-fold higher concentration than the blood and a low accumulation (<10% ID/g) in other organs such as kidneys, liver, lungs, muscle, and spleen.…”

“…Using antibodies against MUC1-C could introduce a more promising strategy for an efficient targeting of MUC1positive cancers. 9,65,137,138 Antibodies raised against shortened glycopeptide structures could elicit the strongest reactivity with MUC1 expressed cells compared to nonglycopeptides. 139 Furthermore, through the connecting of immune cells with tumor cells, bispecific antibodies (bsAbs) containing singlechain variable fragment (scFv) exhibited a potent cytotoxicity for MUC1-positive tumors, and several bsAbs are either under investigation or being approved for clinical trials.…”