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

Bono, Johann S. de; Rha, S. Y.; Stephenson, Joseph; Schultes, Birgit C.; Monroe, P.; Eckhardt, S. Gail; Hammond, Lisa A.; Whiteside, Theresa L.; Nicodemus, Christopher F.; Cermák, J; Rowinsky, Eric K.; Tolcher, Anthony W.

doi:10.1093/annonc/mdh472

Cited by 60 publications

(47 citation statements)

References 26 publications

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“…Tumor-associated MUC1 has been extensively studied as a tumor marker and as a target in cancer therapeutics (28)(29)(30)(31)(32)(33). In an attempt to target MUC1, a variety of anti-MUC1 antibodies have been generated, almost all of which react with epitopes contained within the highly immunogenic tandem 20-amino acid repeat sequence of the MUC1 a chain.…”

Section: Discussionmentioning

confidence: 99%

MUC1/X Protein Immunization Enhances cDNA Immunization in Generating Anti-MUC1 α/β Junction Antibodies that Target Malignant Cells

Rubinstein

Karmely²,

Ziv³

et al. 2006

Cancer Research

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MUC1 has generated considerable interest as a tumor marker and potential target for tumor killing. To date, most antibodies against MUC1 recognize epitopes within the highly immunogenic A chain tandem repeat array. A major shortcoming of such antibodies is that the MUC1 A chain is shed into the peripheral circulation, sequesters circulating antitandem repeat array antibodies, and limits their ability to even reach targeted MUC1-expressing cells. Antibodies recognizing MUC1 epitopes tethered to the cell surface would likely be more effective. MUC1 A subunit binding the membranetethered B subunit provides such an epitope. By use of a novel protocol entailing immunization with cDNA encoding fulllength MUC1 (MUC1/TM) followed by boosting with the alternatively spliced MUC1/X isoform from which the tandem repeat array has been deleted, we generated monoclonal antibodies, designated DMC209, which specifically bind the MUC1 A/B junction. DMC209 is exquisitely unique for this site; amino acid mutations, which abrogate MUC1 cleavage, also abrogate DMC209 binding. Additionally, DMC209 specifically binds the MUC1 A/B junction on full-length MUC1/TM expressed by breast and ovarian cancer cell lines and on freshly obtained, unmanipulated MUC1-positive malignant plasma cells of multiple myeloma. DMC209 is likely to have clinical application by targeting MUC1-expressing cells directly and as an immunotoxin conjugate. Moreover, the novel immunization procedure used in generating DMC209 can be used to generate additional anti-MUC1 A/B junction antibodies, which may, analogously to Herceptin, have cytotoxic activity. Lastly, sequential immunization with MUC1/TM cDNA acting as a nonspecific adjuvant followed by protein of interest may prove to be a generalizable method to yield high-titer specific antibodies. (Cancer Res 2006; 66(23): 11247-53)

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Section: Discussionmentioning

confidence: 99%

MUC1/X Protein Immunization Enhances cDNA Immunization in Generating Anti-MUC1 α/β Junction Antibodies that Target Malignant Cells

Rubinstein

Karmely²,

Ziv³

et al. 2006

Cancer Research

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“…(14,31) Ragupathi et al (31) showed that MUC1 is a poor target for complementmediated lysis of tumor cells, because the sites for complement activation through antigen-antibody complexes are far (14,32) Polymorphic epithelial mucin is considered as one of the attractive tumor antigens for immunotherapy. (33) Several clinical studies using MUC1 tandem repeat domain-based immunogens (34,35) or mAbs (36,37) have been carried out. MUC1 peptide vaccination induced high titers of IgM and IgG andtibodies and, to a lesser extent, CTL responses.…”

Section: Discussionmentioning

confidence: 99%

Anti‐tumor effect of the anti‐KL‐6/MUC1 monoclonal antibody through exposure of surface molecules by MUC1 capping

Doi

Yokoyama²,

Kondo

et al. 2006

Cancer Science

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Human polymorphic epithelial mucin (MUC1) is a heavily glycosylated large protein that is frequently overexpressed on the surface of many human adenocarcinomas. Studies using monoclonal antibodies (mAb) identified MUC1 as a tumorassociated antigen that has been intensely studied as a target for cancer immunotherapy. We previously identified a mouse IgG 1 mAb that recognizes a sialylated sugar chain, designated as KL-6, classified in 'Cluster 9 (MUC1)'. Using the anti-KL-6 mAb, we investigated antitumor effects of anti-MUC1 mAb on breast cancer cell lines expressing MUC1 abundantly. We showed that anti-KL-6 mAb induced capping of MUC1 and facilitated Ecadherin-mediated cell-cell interaction in the breast cancer cell P olymorphic epithelial mucin (MUC1) is a transmembrane glycoprotein with a large mucin-like domain consisting of 20-amino acid core tandem repeats. MUC1 is glycosylated extensively on serine and threonine residues with O-linked carbohydrate chains, many of which end in sialic acid residues. It is normally expressed on the apical surface of glandular epithelial cells in many types of tissue including breast, lung and ovary. MUC1 is also overexpressed in most adenocarcinomas of the breast, lung, ovary and colon, (1)(2)(3) and its expression is correlated with progression of the disease. Even so, the MUC1 molecule has been postulated as a suitable antigen for immunotherapy. Patients with MUC1-positive tumors develop both humoral and cellular immune responses against determinants on the MUC1 antigens. In such patients, major histocompatibility complex (MHC)-unrestricted cytotoxic T lymphocytes (CTL) against poorly glycosylated MUC1 tandem repeats, (6) and anti-MUC1 antibody (7)(8)(9) can be detected. Therefore, to enhance the endogenous immune response to MUC1, vaccination with designed MUC1 or anti-MUC1 monoclonal antibody (mAb)-based therapies have been investigated. However, the glycosylation patterns of MUC1 are highly complex and differ between tumor cells and normal cells and may vary from one tumor cell type to another. (3,10 -12) Moreover, recent evidence suggests that carbohydrates of MUC1 may not be removed during processing of glycoproteins by dendritic cells (DC) and that glycopeptides presented on DC are recognized by T cells. (13) Therefore, antibodies or CTL induced by vaccination with tandem repeat peptides show low reactivity with glycosylated peptides because they bind the protein core of MUC1. (6,14) The immune response against tumors with overexpressed MUC1 is strongly dependent on the glycosylated stretches of MUC1 molecule.We previously established a mouse IgG 1 mAb that recognizes a sialylated sugar chain on lung adenocarcinoma cells, designated Immunohistochemical and flow cytometric studies have defined KL-6 as belonging to 'Cluster 9 (MUC1)' of the lung tumor and differentiation antigens, (16) and the molecule consists of multiple heterogeneous submolecules. (17)(18)(19) We found that there is a natural auto-antibody against KL-6 at high levels in sera from healthy volunteers ...

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“…3), and recent studies have investigated whether such antibodies initiate a vaccinal effect that is characterized by an antitumor cellular immune response. Examples of cytotoxic antibody-induced vaccinal effects from the clinic include patients treated with anti-MUC1 mAbs or anti-HER2/Neu mAbs, who generated MUC1-specific and HER2-specific T-cell responses, respectively (54,55). Because a single course of treatment with anti-CD20 mAb (rituximab) can result in long-lasting, durable responses, it has been hypothesized that treatment with this mAb may also induce a vaccinal effect in patients with lymphoma (56).…”

Section: Antibodies Prime Antitumor Immune Responses: the Vaccinal Efmentioning

confidence: 99%

Fc-Receptor Interactions Regulate Both Cytotoxic and Immunomodulatory Therapeutic Antibody Effector Functions

DiLillo

Ravetch

2015

Cancer Immunology Research

116

115

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Antibodies are now recognized as key therapeutic tools to combat most forms of malignancy. Although the first wave of therapeutic antibodies that emerged over two decades ago directly target tumor cells for killing, a new class of antibody therapies targeting immunoregulatory pathways to boost antitumor immune responses by activating the immune system is poised for clinical success. A notable common characteristic of both classes of therapeutic antibodies is the importance of the IgG Fc domain, which connects the fine specificity of an antibody with immune cells that mediate antibody-triggered effector functions through their engagement of Fc receptor (FcR) family members. It is now clear that multiple variables, including the nature of the target molecules, the local presence of effector cells, and the expression patterns of FcRs, will dictate whether and how an antibody will necessitate interactions with FcRs to mediate optimal therapeutic effects. Thus, through careful in vivo mechanistic analyses of individual therapeutic antibodies, Fc domains engineered for optimal engagement of the appropriate cellular FcRs must be designed to maximize clinical success. Cancer Immunol Res; 3(7); 704-13. Ó2015 AACR.

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

Cited by 60 publications

References 26 publications

MUC1/X Protein Immunization Enhances cDNA Immunization in Generating Anti-MUC1 α/β Junction Antibodies that Target Malignant Cells

MUC1/X Protein Immunization Enhances cDNA Immunization in Generating Anti-MUC1 α/β Junction Antibodies that Target Malignant Cells

Anti‐tumor effect of the anti‐KL‐6/MUC1 monoclonal antibody through exposure of surface molecules by MUC1 capping

Fc-Receptor Interactions Regulate Both Cytotoxic and Immunomodulatory Therapeutic Antibody Effector Functions

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