Anti gC1qR/p32/HABP1 Antibody Therapy Decreases Tumor Growth in an Orthotopic Murine Xenotransplant Model of Triple Negative Breast Cancer

Peerschke, Ellinor I.B.; Stanchina, Elisa de; Chang, Qing; Manova‐Todorova, Katia; Barlas, Afsar; Savitt, Anne G.; Geisbrecht, Brian V.; Ghebrehiwet, Berhane

doi:10.3390/antib9040051

Cited by 6 publications

(14 citation statements)

References 47 publications

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“…In TNBC, gC1qR monoclonal antibody 60.11-treated mice have smaller tumors than control mice. Mechanistically, mice in treatment group had higher expression levels of apoptosis-related markers and decreased CD31 (angiogenesis-related marker) expression ( 21 ). In other words, the antibody targeting gC1qR promoted tumor cell apoptosis and decreased angiogenesis.…”

Section: Potential For Translating Into Clinicmentioning

confidence: 99%

“…gC1qR could reshape the tumor microenvironment (TME) by modulating immune cells and cancer cells, resulting in poor anti-tumor efficacy. The activity of targeting gC1qR has been explored in CAR‐T therapy, monoclonal antibodies and cancer which showed effective anti-tumour immune responses ( 20 , 21 ). Here, we focus on recent advances in the understanding of gC1qR in cancer, review results supporting the role of gC1qR in cancer immunology and illustrate its potential for translation into clinical practice.…”

Section: Introductionmentioning

confidence: 99%

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gC1qR: A New Target for Cancer Immunotherapy

Lei

Qin

et al. 2023

Front. Immunol.

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Although breakthroughs in cancer treatment have been achieved, immunotherapy yields only modest benefits in most patients. There is still a gap in clarifying the immune evasiveness and immune-resistance mechanisms. Identifying other candidate targets for cancer immunotherapy is therefore a clear unmet clinical need. The complement system, a pillar of innate immunity, has recently entered the limelight due to its immunoregulatory functions in the tumor microenvironment (TME). In particular, gC1qR, a receptor for globular heads of C1q, serves as a promising new target and has attracted more attention. gC1qR, also named P32/C1qBP/HABP1, is a multifunctional protein that is overexpressed in various cancers and holds prognostic value. It regulates the tumorigenic, progression and metastatic properties of tumor cells through several downstream signaling pathways, including the Wnt/β-catenin, PKC–NF-κB and Akt/PKB pathways. A few preclinical experiments conducted through gC1qR interventions, such as monoclonal antibody, chimeric antigen receptor T‐cell (CAR‐T) therapy, and tumor vaccination, have shown encouraging results in anticancer activity. The efficacy may rely on the regulatory role on the TME, induction of tumor cells apoptosis and antiangiogenic activity. Nevertheless, the current understanding of the relationship between cancer immunotherapy and gC1qR remains elusive and often contradictory, posing both opportunities and challenges for therapeutic translation in the clinic. In this review, we focus on the current understanding of gC1qR function in cancer immunology and highlight the vital roles in regulating the TME. We also examines the rationale behind targeting gC1qR and discusses the potential for translating into clinical practice.

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Section: Potential For Translating Into Clinicmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

gC1qR: A New Target for Cancer Immunotherapy

Lei

Qin

et al. 2023

Front. Immunol.

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“…Histological studies have shown that gC1qR is expressed on epithelial tumors of diverse origins ( 3 ) and elevated levels of gC1qR have likewise been correlated with poor clinical outcomes in breast cancer patients ( 4 , 5 ). Although these relationships have not been defined as causal, a more contemporary study has shown that anti-gC1qR therapy slows tumor growth in an animal model of breast cancer ( 6 ). This emerging proof-of-concept evidence suggests that therapeutic targeting of cell surface-exposed gC1qR may be beneficial in certain cancers.…”

Section: Introductionmentioning

confidence: 99%

gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII

Zhang

Vontz²,

Kallenberger³

et al. 2022

Front. Immunol.

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The protein gC1qR/C1qBP/HABP-1 plays an essential role in mitochondrial biogenesis, but becomes localized at the cellular surface in numerous pathophysiological states. When this occurs on endothelial cells, surface-exposed gC1qR activates the classical pathway of complement. It also promotes assembly of a multi-protein complex comprised of coagulation factor XII (FXII), pre-kallikrein (PK), and high-molecular weight kininogen (HMWK) that activates the contact system and the kinin-generating system. Since surface-exposed gC1qR triggers intravascular inflammatory pathways, there is interest in identifying molecules that block gC1qR function. Here we further that objective by reporting the outcome of a structure/function investigation of gC1qR, its interactions with FXII, and the impact of a panel of monoclonal anti-gC1qR antibodies on FXII binding to gC1qR. Although deletion mutants have been used extensively to assess gC1qR function, none of these proteins have been characterized structurally. To that end, we determined a 2.2 Å resolution crystal structure of a gC1qR mutant lacking both of its acidic loops, but which retained nanomolar-affinity binding to FXII and FXIIa. This structure revealed that the trimeric gC1qR assembly was maintained despite loss of roughly thirty residues. Characterization of a novel panel of anti-gC1qR monoclonal antibodies identified several with biochemical properties distinct from previously described antibodies, as well as one which bound to the first acidic loop of gC1qR. Intriguingly, we found that each of these antibodies could partly inhibit binding of FXII and FXIIa to gC1qR. Based on these results and previously published studies, we offer new perspectives for developing gC1qR inhibitors.

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“…The role of complement and, in particular, complement receptors in mouse models of triple-negative breast cancer are examined in two particularly interesting and innovative articles [7,8]. This form of cancer lacks any of the common and targetable hormone receptors and is therefore particularly resistant to most conventional treatments.…”

mentioning

confidence: 99%

“…Teams led by Peerschke and Ghebrehiwet have been among the leading groups studying the biology and immunology of C1q and its receptors. In this issue, they have investigated how targeting the globular receptor to C1q (gC1qR) with a specific neutralizing mAb affects the growth of breast cancer cells in a mouse xenotranplant model of triplenegative breast cancer in which the gC1qR is upregulated on the tumor cells [8]. The investigators made use of a variety of elegant immunostaining techniques along with measures of tumor growth and report, for the first time, in vivo proof of principle for suppression of growth of triple-negative breast cancer cells accomplished by targeting gC1qR with a neutralizing mAb.…”

mentioning

confidence: 99%