Evaluation of a novel monoclonal antibody against tumor-associated MUC1 for diagnosis and prognosis of breast cancer

Abstract

There is still a great unmet medical need concerning diagnosis and treatment of breast cancer which could be addressed by utilizing specific molecular targets. Tumor-associated MUC1 is expressed on over 90 % of all breast cancer entities and differs strongly from its physiological form on epithelial cells, therefore presenting a unique target for breast cancer diagnosis and antibody-mediated immune therapy. Utilizing an anti-tumor vaccine based on a synthetically prepared glycopeptide, we generated a monoclonal antibody (mAb) GGSK-1/30, selectively recognizing human tumor-associated MUC1. This antibody targets exclusively tumor-associated MUC1 in the absence of any binding to MUC1 on healthy epithelial cells thus enabling the generation of breast tumor-specific radiolabeled immune therapeutic tools.Methods: MAb GGSK-1/30 was used for immunohistochemical analysis of human breast cancer tissue. Its desferrioxamine (Df')-conjugate was synthesized and labelled with 89Zr. [89Zr]Zr-Df'-GGSK-1/30 was evaluated as a potential PET tracer. Binding and pharmacokinetic properties of [89Zr]Zr-Df'-GGSK-1/30 were analyzed in vitro using human and murine cell lines that express tumor-associated MUC1. Self-generated primary murine breast cancer cells expressing human tumor-associated MUC1 were transplanted subcutaneously in wild type and human MUC1-transgenic mice. The pharmacology of [89Zr]Zr-Df'-GGSK-1/30 was investigated using breast tumor-bearing mice in vivo by PET/MRT imaging as well as by ex vivo organ biodistribution analysis.Results: The mAb GGSK-1/30 stained specifically human breast tumor tissue and can be possibly used to predict the severity of disease progression based on the expression of the tumor-associated MUC1. For in vivo imaging, the Df'-conjugated mAb was radiolabeled with a radiochemical yield of 60 %, a radiochemical purity of 95 % and an apparent specific activity of 6.1 GBq/µmol. After 7 d, stabilities of 84 % in human serum and of 93 % in saline were observed. In vitro cell studies showed strong binding to human tumor-associated MUC1 expressing breast cancer cells. The breast tumor-bearing mice showed an in vivo tumor uptake of >50 %ID/g and clearly visible specific enrichment of the radioconjugate via PET/MRT.Principal conclusions: Tumor-associated MUC1 is a very important biomarker for breast cancer next to the traditional markers estrogen receptor (ER), progesterone receptor (PR) and HER/2-neu. The mAb GGSK-1/30 can be used for the diagnosis of over 90% of breast cancers, including triple negative breast cancer based on biopsy staining. Its radioimmunoconjugate represents a promising PET-tracer for breast cancer imaging selectively targeting breast cancer cells.

Patterns of biomarker expression in patients treated with primary endocrine therapy – a unique insight using core needle biopsy tissue microarray

“…Mucin-1 is an epithelial cell surface protein that is overexpressed in up to 90% of breast cancers [ 34 ]. MUC1 overexpression has been associated with shorter BCSS in invasive breast cancer but in cases primarily receiving surgical treatment [ 35 , 36 ] and not specific to older women.…”

Targeting Glycans and Heavily Glycosylated Proteins for Tumor Imaging

“…Alternatively, GGSK-1/30, which is a murine mAb specific for an alternative MUC1 glycoprotein epitope, was conjugated to 89 Zr and evaluated for combined PET/MRI imaging of breast cancer-bearing human MUC1-expressing transgenic mice [54]. At 72 h post-injection, administration of 89 Zr-GGSK-1/30 revealed high tracer tumor uptake with lower uptake in excreting organs and healthy mammary tissue, providing high-contrast tumor delineation.…”

“…At 72 h post-injection, administration of 89 Zr-GGSK-1/30 revealed high tracer tumor uptake with lower uptake in excreting organs and healthy mammary tissue, providing high-contrast tumor delineation. Considering its expression in 90% of breast tumors, including triple-negative breast carcinomas, GGSK-1/30 also seems a promising targeting moiety for pan-breast cancer detection [54].…”

“…In cancer, aberrant glycosylation is mainly characterized by increased N -glycan branching, augmented O -glycan density, incomplete glycan synthesis, and, in more advanced cancers, synthesis of neo-glycan determinants that carry large amounts of sialic acids or fucose residues [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61...…”

Antibody–Drug Conjugate to Treat Meningiomas

“…Antibody–drug conjugates (ADCs) have been developed to treat cancers or tumors [ 19 , 20 , 21 , 22 ] and have demonstrated promising clinical efficacy and minimal adverse effects [ 23 , 24 , 25 , 26 ]. For instance, the gemtuzumab ozogamicin (anti-CD33 mAb-N-acetyl gamma calicheamicin conjugate) [ 27 , 28 ] for acute myeloid leukemia treatment, traztuzumab deruxtecan (anti-HER2 mAb-topoisomerase I inhibitor) [ 29 ] and trastuzumab emtansine (anti-HER2 mAb-Mertansine DM1 conjugate) [ 30 , 31 ] for chemotherapy refractory or advanced HER2-positive breast cancer, brentuximab vedotin (anti-CD30 mAb-MMAE conjugate) [ 32 , 33 ] for relapsed Hodgkin lymphoma, and 131 I-Tositumomab (anti-CD20 mAb-Iodine 131) [ 34 ] and 90 Y-Ibritumomab tiuxetan (anti-CD20 mAb-Yttrium-90) [ 35 ] for non-Hodgkin lymphoma have been approved by the FDA and used in clinics. Compared to standard chemotherapies, ADCs can specifically target cancer cells, deliver highly cytotoxic payloads, and reduce adverse effects.…”