Immunization with a Synthetic Human MUC1 Glycopeptide Vaccine against Tumor‐Associated MUC1 Breaks Tolerance in Human MUC1 Transgenic Mice

Stergiou, Natascha; Glaffig, Markus; Jonuleit, Helmut; Schmitt, Edgar; Kunz, Horst

doi:10.1002/cmdc.201700387

Cited by 28 publications

(27 citation statements)

References 44 publications

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“…51 The MUC1 immune tolerance in MUC1.Tg mice leads to great difficulties in eliciting effective antibody responses against the protective MUC1 epitopes. 52–54 With our first generation vaccine construct Q β -MUC1 5–8, we observed significantly weaker binding of MUC1 expressing tumor cells by postimmune sera from Tg mice compared to those from WT mice despite similar levels of total antibodies elicited against the immunizing MUC1 structures 1–4. Similar phenomena of low tumor cell binding were observed in clinical studies of MUC1 based vaccines in human patients.…”

Section: Discussionmentioning

confidence: 86%

Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice

Yin

McKay

et al. 2018

J. Am. Chem. Soc.

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Human mucin-1 (MUC1) is a highly attractive antigen for the development of anticancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUCl antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qβ carrier with MUC1 glycopeptides containing 20–22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but nonprotective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qβ-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qβ-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities toward human breast cancer tissues, suggesting its high translational potential.

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Section: Discussionmentioning

confidence: 86%

Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice

Yin

McKay

et al. 2018

J. Am. Chem. Soc.

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“…Investigators in the Kunz laboratory have chemically synthesized a wide range of glycopeptides based on the TR of MUC1 and have evaluated various formulations of these (containing factors to recruit innate immunity and/or CD4 help) for antibody induction in WT mice [ 35 , 36 ]. Some of these new antibodies show specificity for the tumour MUC1 glycoforms [ 37 ] and humoral and cellular immune responses to one vaccine formulation (1TR carrying Tn and STn bound to tetanus toxin) have been detected in MUC1 transgenic mice where human MUC1 is expressed from the MUC1 promoter [ 38 ].…”

Section: Preclinical Studies and Combination Therapiesmentioning

confidence: 99%

“…When presented by DCs in MUC1 transgenic mice, MUC- reactive CD4 T-cell responses have been documented [ 28 , 50 ], along with the induction of humoral immunity [ 28 , 50 ] . Moreover, several investigators have demonstrated that MUC1 vaccines carrying the Tn and/or STn glycan are not subject to self-tolerance in MUC1 transgenic mice [ 38 , 46 , 51 ].…”

Section: Applying Research Findings To Immunotherapeutic Strategiesmentioning

confidence: 99%

Latest developments in MUC1 immunotherapy

Taylor‐Papadimitriou

Burchell

Graham

et al. 2018

Biochemical Society Transactions

108

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Currently, there is renewed interest in attempting to recruit the host immune system to eliminate cancers, and within this renewed activity, MUC1 continues to arouse interest. MUC1 has been considered a possible therapeutic target for the past 30 years as it is up-regulated, aberrantly glycosylated and its polarization is lost in many adenocarcinomas. Moreover, MUC1 is expressed by some haematopoietic cancers, including acute myeloid leukaemia and myeloma. Although multiple clinical trials have been initiated and immune responses have been documented, effective clinical benefit worthy of approval for general application has not as yet been achieved. However, this does not appear to have quelled the interest in MUC1 as a therapeutic target, as shown by the increase in the number of MUC1-based clinical trials initiated in 2017 ( Figure 1). As with all translational studies, incorporating new relevant research findings into therapeutic strategy is difficult. Decisions are made to commit to a specific strategy based on the information and data available when the trial is initiated. However, the time required for preclinical studies and early trials can render the founding concept not always appropriate for proceeding to a larger definitive trial. Here, we summarize the attempts made, to date, to bring MUC1 into the world of cancer immunotherapy and discuss how research findings regarding MUC1 structure and function together with expanded knowledge of its interactions with the tumour environment and immune effector cells could lead to improved therapeutic approaches. Figure 1.Number of MUC1-targeted trials initiated each year.

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“…The unlinked adjuvant/ antigen delivery may lead to activation of DC that have not been loaded with antigen and loading with antigen of DC that have not been activated by adjuvant. Therefore a methodology that leads to efficient antigen loading and DC activation of the same DC, includes a conjugation of antigen and adjuvant (Abdel-Aal et al, 2014;Liu et al, 2015;Stergiou et al, 2017;Zom et al, 2016) for efficient uptake and activation. Targeted delivery via DEC2015 (Birkholz et al, 2010) also displays improved antigen uptake by DCs through the mannose receptor (Morse et al, 2011), and other strategies exists and can target delivery to a given cell type (Tacken et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Linking T cell epitopes to a common linear B cell epitope: A targeting and adjuvant strategy to improve T cell responses

Mangsbo

Fletcher

Maren

et al. 2018

Molecular Immunology

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Immune complexes are potent mediators of cellular immunity and have been extensively studied for their disease mediating properties in humans and for their role in anti-cancer immunity. However, a viable approach to use antibody-complexed antigen as vehicle for specific immunotherapy has not yet reached clinical use. Since virtually all people have endogenous antibodies against tetanus toxoid (TTd), such commonly occurring antibodies are promising candidates to utilize for immune modulation. As an initial proof-of-concept we investigated if anti-tetanus IgG could induce potent cross-presentation of a conjugate with SIINFEKL, a MHC class I presented epitope of ovalbumin (OVA), to TTd. This protein conjugate enhanced OVA-specific CD8+ T cell responses when administrated to seropositive mice. Since TTd is poorly defined, we next investigated whether a synthetic peptide-peptide conjugate, with a chemically defined linear B cell epitope of tetanus toxin (TTx) origin, could improve cellular immune responses. Herein we identify one linear B cell epitope, here after named MTTE thru a screening of overlapping peptides from the alpha and beta region of TTx, and by assessment of the binding of pooled IgG, or individual human IgG from high-titer TTd vaccinated donors, to these peptides. Subsequently, we developed a chemical protocol to synthesize defined conjugates containing multiple copies of MTTE covalently attached to one or more T cell epitopes of choice. To demonstrate the potential of the above approach we showed that immune complexes of anti-MTTE antibodies with MTTE-containing conjugates are able to induce DC and T cell activation using model antigens.

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Immunization with a Synthetic Human MUC1 Glycopeptide Vaccine against Tumor‐Associated MUC1 Breaks Tolerance in Human MUC1 Transgenic Mice

Cited by 28 publications

References 44 publications

Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice

Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice

Latest developments in MUC1 immunotherapy

Linking T cell epitopes to a common linear B cell epitope: A targeting and adjuvant strategy to improve T cell responses

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