Characterization of an Anti-MUC1 Monoclonal Antibody with Potential as a Cancer Vaccine

Qi, Weimin; Schultes, Birgit C.; Liú, Dan; Kuzma, Michelle; Decker, Wendy; Madiyalakan, Ragupathy

doi:10.1089/15368590152740716

Cited by 21 publications

(20 citation statements)

References 32 publications

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“…In 2016, Movahedin et al published the co-crystal structure of AR20.5 bound with APDT(Tn)RPAP [ 58 ] ( Figure 4 ). AR20.5 (OncoQuest Inc., Edmonton, AB, Canada), is a murine anti-MUC1 monoclonal antibody (IgG 1 ) generated with MUC1 from an ovarian cancer patient [ 59 ]. The 6-amino acid epitope (DTRPAP) with a single glycosylation at Thr within the tandem repeat represents the minimal epitope AR20.5 recognizes.…”

Section: Published Co-crystal Structures: 3 Hypothesized Models Ofmentioning

confidence: 99%

Epitopes of MUC1 Tandem Repeats in Cancer as Revealed by Antibody Crystallography: Toward Glycopeptide Signature-Guided Therapy

Zhou

Huang

et al. 2018

Molecules

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Abnormally O-glycosylated MUC1 tandem repeat glycopeptide epitopes expressed by multiple types of cancer have long been attractive targets for therapy in the race against genetic mutations of tumor cells. Glycopeptide signature-guided therapy might be a more promising avenue than mutation signature-guided therapy. Three O-glycosylated peptide motifs, PDTR, GSTA, and GVTS, exist in a tandem repeat HGVTSAPDTRPAPGSTAPPA, containing five O-glycosylation sites. The exact peptide and sugar residues involved in antibody binding are poorly defined. Co-crystal structures of glycopeptides and respective monoclonal antibodies are very few. Here we review 3 groups of monoclonal antibodies: antibodies which only bind to peptide portion, antibodies which only bind to sugar portion, and antibodies which bind to both peptide and sugar portions. The antigenicity of peptide and sugar portions of glyco-MUC1 tandem repeat were analyzed according to available biochemical and structural data, especially the GSTA and GVTS motifs independent from the most studied PDTR. Tn is focused as a peptide-modifying residue in vaccine design, to induce glycopeptide-binding antibodies with cross reactivity to Tn-related tumor glycans, but not glycans of healthy cells. The unique requirement for the designs of antibody in antibody-drug conjugate, bi-specific antibodies, and chimeric antigen receptors are also discussed.

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Section: Published Co-crystal Structures: 3 Hypothesized Models Ofmentioning

confidence: 99%

Epitopes of MUC1 Tandem Repeats in Cancer as Revealed by Antibody Crystallography: Toward Glycopeptide Signature-Guided Therapy

Zhou

Huang

et al. 2018

Molecules

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“…Serum levels of MUC1 were determined by sandwich ELISA where mAb-AR20.5 (recognizing DTRPAP epitope) was used for capture and detection [42]. 96 well plates were coated with mAb-AR20.5 (2.5 μg/ml) overnight at 4°C, then blocked with 3% BSA in PBS/ 0.06% Thimoseral, followed by incubation with MUC1 standards or serum samples for 1hr at RT.…”

Section: Enzyme-linked Immunosorbent Assay For Muc1mentioning

confidence: 99%

Combination of mAb-AR20.5, anti-PD-L1 and PolyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors

Mehla

Tremayne²,

Grunkemeyer

et al. 2017

Cancer Immunol Immunother

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A substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced immunosuppression renders these responses ineffective. The current study explores a novel therapeutic combination wherein tumor-bearing hosts can be immunologically primed with their own antigen, through opsonization with a tumor antigen-targeted antibody, mAb-AR20.5. We evaluated the efficacy of immunization with this antibody in combination with PolyICLC and anti-PD-L1. The therapeutic combination of mAb-AR20.5 + anti-PD-L1 + PolyICLC induced rejection of human MUC1 expressing tumors and provided a long-lasting, MUC1-specific cellular immune response, which could be adoptively transferred and shown to provide protection against tumor challenge in human MUC1 transgenic (MUC.Tg) mice. Furthermore, antibody depletion studies revealed that CD8 cells were effectors for the MUC1-specific immune response generated by the mAb-AR20.5 + anti-PD-L1 + PolyICLC combination. Multichromatic flow cytometry data analysis demonstrated a significant increase over time in circulating, activated CD8 T cells, CD3CD4CD8(DN) T cells, and mature dendritic cells in mAb-AR20.5 + anti-PD-L1 + PolyICLC combination-treated, tumor-bearing mice, as compared to saline-treated control counterparts. Our study provides a proof of principle that an effective and long-lasting anti-tumor cellular immunity can be achieved in pancreatic tumor-bearing hosts against their own antigen (MUC1), which can be further potentiated using a vaccine adjuvant and an immune checkpoint inhibitor.

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“…The assay was performed according to the procedures and conditions previously described [47,48]. Each well of the ELISA plate (Immuno module; Nunc Intermed, Kamstrup, Denmark) was coated with 50 ll of untreated or desialylated gp in 0.05 M carbonate buffer (pH 9.6) overnight at 4°C.…”

Section: Microtiter Plate Enzyme-linked Immunosorbent Assay (Elisa)mentioning

confidence: 99%

Further characterization of the binding properties of two monoclonal antibodies recognizing human Tn red blood cells

et al. 2005

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The terminal alpha anomeric Ga1NAc residue is an essential sugar for the Tn glycotope, human blood group A determinant, and Forssman antigen. In a previous study [King M.J., Parson S.F., Wu A,M., Jones N., Transfusion 31: 142-149, 1991] we defined two monoclonal antibodies (MoAbs, BRIC66 and BRIC111) reacting with human Tn red blood cells. However, more advanced studies of these two MoAbs were hampered by the lack of availability of Gal/GalNAc related glycotopes. In order to use these antibodies as powerful probes to elucidate structural changes during life processes, we have characterized in detail the combining sites of these two MoAbs using enzyme-linked immunosorbent (ELISA) and inhibition assays with an extended glycan/ligand collection. From the results, it has been established that BRIC66 demonstrated multiple specificities and its reactivity towards glycotopes was defined as: Ga1NAc alpha1-->Ser/Thr (Tn) > or = Ga1NAc alpha1-->3(LFuc alpha1-->2)Gal (Ah) > Ga1NAcalpha1-->3Galbeta1-->4Glc (AL) > Ga1NAalpha1-->3Gal (A) GalNAc alpha1-->3GalNAc >> Gal or Glc. Another MoAb, BRIC111, mainly bound Tn-glycophorin. The best ligand for this MoAb was Tn-containing glycopeptides (M.W. < 3.0 x 10(3) Da) from asialo ovine salivary mucin (OSM), which was approximately 70 and 58 times more active than Ga1NAc and monomeric Ga1NAc alpha1-->Ser/Thr (Tn), respectively, suggesting that the active glycotopes present in glycophorin for BRIC111 binding also exist in OSM. The N-acetyl group at carbon-2 and configuration at carbon-2 and carbon-4 of the alpha anomeric Ga1NAc are required for the binding of either MoAb. Identification of these binding properties should aid in the selection of these MoAbs and the conditions required for biological studies and clinical applications.

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Characterization of an Anti-MUC1 Monoclonal Antibody with Potential as a Cancer Vaccine

Cited by 21 publications

References 32 publications

Epitopes of MUC1 Tandem Repeats in Cancer as Revealed by Antibody Crystallography: Toward Glycopeptide Signature-Guided Therapy

Epitopes of MUC1 Tandem Repeats in Cancer as Revealed by Antibody Crystallography: Toward Glycopeptide Signature-Guided Therapy

Combination of mAb-AR20.5, anti-PD-L1 and PolyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors

Further characterization of the binding properties of two monoclonal antibodies recognizing human Tn red blood cells

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