作者: O'Connell, Kelly A ; Tremayne, Jarrod ; Caffrey, Thomas C ; Singh, Pankaj K ; Schultes, Birgit C ; Yu, Fang ; Zhu, Xinyi ; Grunkemeyer, James A ; Mehla, Kamiya ; Steele, Maria M ; Hollingsworth, Michael A ; Madiyalakan, Ragupathy ; Nicodemus, Christopher F

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, CD3⁺CD4^-CD8^-(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.

2004-12-01·Annals of Oncology1区 · 医学

Phase I trial of a murine antibody to MUC1 in patients with metastatic cancer: evidence for the activation of humoral and cellular antitumor immunity

1区 · 医学

Article

作者: P. Monroe ; C. F. Nicodemus ; S Gail Eckhardt ; B. C. Schultes ; E. K. Rowinsky ; T. L. Whiteside ; L. A. Hammond ; A. W. Tolcher ; J. M. Cermak ; S. Y. Rha ; J. S. de Bono ; J. Stephenson

BACKGROUNDBrevaRex mAb-AR20.5 is a murine anti-MUC1 monoclonal antibody generated to induce MUC1 antigen-specific immune responses through the formation of immune complexes with circulating MUC1 and/or MUC1-expressing tumor cells that may target these immune complexes (IC) to receptors on dendritic cells (DCs).PATIENTS AND METHODSA phase I study focusing on safety and immunology evaluated 1, 2 and 4-mg doses. Seventeen patients with MUC1-positive cancers received intravenous infusions of the antibody over 30 min on weeks 1, 3, 5, 9, 13 and 17 of treatment.RESULTSmAb-AR20.5 was well-tolerated, not associated with dose-limiting toxicity, and did not induce hypersensitivity reactions. Overall, five of 15 evaluable patients developed human anti-mouse antibodies (HAMA), five developed anti-idiotypic antibodies (Ab2) and seven developed anti-MUC1 antibodies. Immune responses were most prominent in the 2-mg dose cohort for all parameters tested, and treatment-emergent MUC1-specific T-cell responses were detected in five of 10 evaluable patients treated with mAb-AR20.5.CONCLUSIONSThe injection of a murine antibody to MUC1 induces MUC1-specific immune responses in advanced cancer patients. Anti-MUC1 antibody increases correlated with decrease or stabilization of CA15.3 levels (P=0.03). The 2-mg dose of mAb-AR20.5 showed strongest biological activity, and will be evaluated in future efficacy trials.

2001-10-01·Hybridoma and Hybridomics

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

Article

作者: Schultes, Birgit C. ; Decker, Wendy ; Qi, Weimin ; Madiyalakan, Ragupathy ; Kuzma, Michelle ; Liu, Dan

The monoclonal antibody (MAb) AR20.5 is a murine MAb, generated against the tandem repeat protein backbone of the tumor-associated antigen MUC1. MAb AR20.5 reacts strongly with either the soluble form or the cell surface epitope of MUC1 on many human cancer cell lines. It also reacts with a 23-amino acid MUC1 peptide, E23, which includes the core tandem repeat sequence. Epitope mapping confirmed that MAb AR20.5 recognizes a minimum of six residues with the sequence DTRPAP. Inhibition of glycosylation of MUC1 resulted in decreased binding of MAb AR20.5 to cell surface MUC1, suggesting that MAb AR20.5 binding is carbohydrate dependent. The antibody was studied in a human PBL-SCID/beige mouse model to evaluate its effect on progression of NIH:OVARCAR-3 tumors. Tumor reduction was observed in mice injected with MAb AR20.5, but not in mice treated with control murine antibody or PBS (p < 0.001 and p < 0.05, respectively). An anti-tumor effect could also be demonstrated in a CB6F1 mouse model with the MUC1 transfectoma 413BCR.

项与 MAb-AR20.5 相关的新闻（医药）

2023-08-21

·PRNewswire

CanariaBio Achieves Significant Milestone with FDA's Orphan Drug Designation for MAb-AR20.5 Targeting Pancreatic Cancer

The investigational monoclonal antibody becomes the first to target Mucin 1 (MUC1) and receive this designation. PYEONGTAEK, South Korea, Aug. 21, 2023 /PRNewswire/ -- CanariaBio Inc., a clinical-stage biopharmaceutical company focused on the development and commercialization of innovative immunotherapies for cancer, announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to its investigational drug product, MAb-AR20.5, an IgG1k type murine monoclonal antibody that binds specifically to the circulating and tumor-associated antigen (MUC1) expressed ubiquitously on pancreatic cancer cells. This milestone marks the first monoclonal antibody targeting Mucin 1 (MUC1) to receive this designation for pancreatic cancer. Continue Reading Pancreatic cancer remains one of the most challenging malignancies to treat, with limited therapeutic options available. The MAb-AR20.5 has shown potential in early studies, by inducing MUC-1-specific immune responses in cancer patients with advanced disease. This specific targeting aims to provide a more focused and potentially more effective treatment strategy for patients diagnosed with this aggressive disease. "Receiving Orphan Drug Designation for MAb-AR20.5 is a significant milestone for CanariaBio Inc. and speaks to the potential promise of this novel therapeutic approach," said Mike Na, the CEO of CanariaBio Inc. "We are deeply committed to advancing innovative treatments for patients with pancreatic cancer and remain hopeful that MAb-AR20.5 will offer a new lifeline for those affected." Orphan Drug Designation is granted by the FDA to drugs and biologics intended for the treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. This designation provides certain benefits, including tax credits, user fee waivers, and eligibility for seven years of marketing exclusivity. CanariaBio Inc. is planning to initiate clinical trials to assess the safety and efficacy of MAb-AR20.5 in patients with pancreatic cancer. More details about the upcoming studies and trial sites will be made available in the coming months. About CanariaBio Inc. Canariabio Inc. is a clinical-stage biopharmaceutical company dedicated to the development and commercialization of innovative cancer biotherapeutics. CanariaBio's technology platform includes a portfolio of tumor antigen-specific monoclonal antibodies targeting CA-125, MUC1, PSA, and Her2/neu.The company is exploring the therapeutic potential of these antibodies as indirect immunizers in combination with other immune-modulating drugs or drug combinations to address unmet medical needs in oncology. Its flagship product, oregovomab, a monoclonanl antibody targeting MUC16 being developed in combination chemotherapy drugs (paclitaxel and carboplatin) for the treatment of ovarian cancer is in the advanced Phase 3 stage. With a skilled team and innovative technologies, Canariabio is reshaping the landscape of cancer treatment. SOURCE CanariaBio Inc.