Targeted glycan degradation potentiates the anticancer immune response in vivo

Gray, Melissa A.; Stanczak, Michal A.; Mantuano, Natália Rodrigues; Xiao, Han; Pijnenborg, Johan F. A.; Malaker, Stacy A.; Miller, Caitlyn L.; Weidenbacher, Payton A.; Tanzo, Julia T.; Ahn, Green; Woods, Elliot C.; Läubli, Heinz; Bertozzi, Carolyn R.

doi:10.1038/s41589-020-0622-x

Cited by 242 publications

(274 citation statements)

References 56 publications

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“…This hypothesis is in line with previous literature reporting that ADCC efficacy can be regulated by the strength of antigen–antibody interactions [29] or antibody–Fc receptor interactions [22,30] . Because the enhanced affinity of anti‐CCR4 antibody for CD16a is due to the defucosylation of the N‐glycans in its Fc region, [22] recent advances in in vivo glycoengineering [31–33] might be applicable for enhancing the efficacy of the Fc‐ARM strategy through modification of the glycans on endogenous antibodies.…”

supporting

confidence: 86%

Fc‐Binding Antibody‐Recruiting Molecules Targeting Prostate‐Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement**

et al. 2020

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Synthetic small molecules that redirect endogenous antibodies to target cells are promising drug candidates because they overcome the potential shortcomings of therapeutic antibodies, such as immunogenicity. Previously, we reported a novel class of bispecific molecules targeting the antibody Fc region and folate receptor, named Fc-binding antibody-recruiting molecules (Fc-ARMs). Fc-ARMs can theoretically recruit most endogenous antibodies, inducing cancer cell elimination via antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we describe new Fc-ARMs that target prostate cancer (Fc-ARM-Ps). Fc-ARM-Ps recruited antibodies to cancer cells expressing prostate membrane-specific antigen but did so with lower efficiency compared with Fc-ARMs targeting folate receptor. Upon recruitment by Fc-ARM-P, defucosylated antibodies efficiently activated natural killer cells and induced ADCC, whereas antibodies with intact N-glycans did not. The results suggest that the affinity between recruited antibodies and CD16a, a type of Fc receptor expressed on immune cells, could be a key factor controlling immune activation in the Fc-ARM strategy. File list (2) download file view on ChemRxiv KS&MH manuscript_vf.pdf (1.13 MiB) download file view on ChemRxiv KS&MH, SI_vf.pdf (779.54 KiB)

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supporting

confidence: 86%

Fc‐Binding Antibody‐Recruiting Molecules Targeting Prostate‐Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement**

et al. 2020

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“…Beatson et al used primary tumour and immune cells, both extracted from patient samples, showing the importance of the interaction between SIGLEC-9 and mucin-derived truncated antigens for the immunosuppressive phenotype of TAM, as described in Section 4 [ 47 , 71 ]. In another study, Gray et al employed syngeneic BC models to assess the potential of targeting glycan degradation to improve anticancer immune response [ 84 ]. Sialidase-targeted BC cells induced an increase in total tumour leukocytes, with a reduced number of CD206+ macrophages.…”

Section: Glycan-lectin Interactions: Novel Targets For Tumour-assomentioning

confidence: 99%

“…These studies support the possibility of switching macrophage phenotype by targeting immunosuppressive glycan-lectin interactions. The authors showed that the recognition of sialic acid by macrophages was mediated by murine SIGLEC-E [ 84 ], a functional orthologue of human Siglec-9. Thus, the clinical translation of these findings will be dependent on their confirmation in a human setting.…”

Section: Glycan-lectin Interactions: Novel Targets For Tumour-assomentioning

confidence: 99%

Cracking the Breast Cancer Glyco-Code through Glycan-Lectin Interactions: Targeting Immunosuppressive Macrophages

Lopes

Correia

Palma

et al. 2021

IJMS

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The immune microenvironment of breast cancer (BC) is composed by high macrophage infiltrates, correlated with the most aggressive subtypes. Tumour-associated macrophages (TAM) within the BC microenvironment are key regulators of immune suppression and BC progression. Nevertheless, several key questions regarding TAM polarisation by BC are still not fully understood. Recently, the modulation of the immune microenvironment has been described via the recognition of abnormal glycosylation patterns at BC cell surface. These patterns rise as a resource to identify potential targets on TAM in the BC context, leading to the development of novel immunotherapies. Herein, we will summarize recent studies describing advances in identifying altered glycan structures in BC cells. We will focus on BC-specific glycosylation patterns known to modulate the phenotype and function of macrophages recruited to the tumour site, such as structures with sialylated or N-acetylgalactosamine epitopes. Moreover, the lectins present at the surface of macrophages reported to bind to such antigens, inducing tumour-prone TAM phenotypes, will also be highlighted. Finally, we will discuss and give our view on the potential and current challenges of targeting these glycan-lectin interactions to reshape the immunosuppressive landscape of BC.

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“…142 Recently, HER2-targeted bacterial sialidase was tested in vivo in syngeneic mice and showed efficacy. 143 Currently, a humanized version of this tumor-targeted sialidase is in clinical development and the toxicity profile needs to be further tested.…”

Section: Targeting Glycan-receptor Interactions To Improve Cancer Immmentioning

confidence: 99%

Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy

Mantuano

Natoli

Zippelius

et al. 2020

J Immunother Cancer

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During oncogenesis, tumor cells present specific carbohydrate chains that are new targets for cancer immunotherapy. Whereas these tumor-associated carbohydrates (TACA) can be targeted with antibodies and vaccination approaches, TACA including sialic acid-containing glycans are able to inhibit anticancer immune responses by engagement of immune receptors on leukocytes. A family of immune-modulating receptors are sialic acid-binding Siglec receptors that have been recently described to inhibit antitumor activity mediated by myeloid cells, natural killer cells and T cells. Other TACA-binding receptors including selectins have been linked to cancer progression. Recent studies have shown that glycan-lectin interactions can be targeted to improve cancer immunotherapy. For example, interactions between the immune checkpoint T cell immunoglobulin and mucin-domain containing-3 and the lectin galectin-9 are targeted in clinical trials. In addition, an antibody against the lectin Siglec-15 is being tested in an early clinical trial. In this review, we summarize the previous and current efforts to target TACA and to inhibit inhibitory immune receptors binding to TACA including the Siglec-sialoglycan axis.

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Targeted glycan degradation potentiates the anticancer immune response in vivo

Cited by 242 publications

References 56 publications

Fc‐Binding Antibody‐Recruiting Molecules Targeting Prostate‐Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement**

Fc‐Binding Antibody‐Recruiting Molecules Targeting Prostate‐Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement**

Cracking the Breast Cancer Glyco-Code through Glycan-Lectin Interactions: Targeting Immunosuppressive Macrophages

Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy

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