ArticleJCI insight2022
Trastuzumab/pertuzumab combination therapy stimulates antitumor responses through complement-dependent cytotoxicity and phagocytosis.
Article in JCI insight, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.
- C1q as a target molecule to treat human disease: What do mouse studies teach us?Frontiers in immunology · 2022Pooled it
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- Endogenous neoantigen-specific antibodies mediate antitumor responses and determine vaccine efficacy.Journal for immunotherapy of cancer · 2026Article
- Development of a STEAP1-Targeted Prostate Cancer Specific Antibody Drug Conjugate Platform with Immunostimulatory Properties.Research square · 2026Article
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- Complement system in cancer: friend or foe of immunotherapy.Journal for immunotherapy of cancer · 2026Review
- Breast Cancer Treatments: Drugs Targeting the PI3K/AKT/mTOR Pathway, TNBC Therapy and Future Directions: A Review.Life (Basel, Switzerland) · 2025Review
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- Sialylated CD43 is a glyco-immune checkpoint for macrophage phagocytosis.bioRxiv : the preprint server for biology · 2025Article
- Effective extracellular payload release and immunomodulatory interactions govern the therapeutic effect of trastuzumab deruxtecan (T-DXd).Nature communications · 2025Article
- Diagnostic and therapeutic advances for HER2-expressing or amplified gynecologic cancers.Gynecologic oncology · 2025Review
- Molecular Subtypes and Mechanisms of Breast Cancer: Precision Medicine Approaches for Targeted Therapies.Cancers · 2025Review
- Directed-Complement Activation as a Novel Immunotherapeutic Approach for HER2-Breast Cancer.ImmunoTargets and therapy · 2025Article
- Optimising Monoclonal Antibody Drug Development for Inflammatory Bowel Disease.Clinical and experimental gastroenterology · 2025Review
- Depicting Biomarkers for HER2-Inhibitor Resistance: Implication for Therapy in HER2-Positive Breast Cancer.Cancers · 2024Review
- Fc-Fc interactions and immune inhibitory effects of IgG4: implications for anti-PD-1 immunotherapies.Journal for immunotherapy of cancer · 2024Article
- Joint multi-omics discriminant analysis with consistent representation learning using PANDA.Research square · 2024Article
- Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Two HER2-specific mAbs, trastuzumab and pertuzumab (T+P), combined with chemotherapy comprise standard-of-care treatment for advanced HER2+ breast cancers (BC). While this antibody combination is highly effective, its synergistic mechanism-of-action (MOA) remains incompletely understood. Past studies have suggested that the synergy underlying this combination occurs through the different mechanisms elicited by these antibodies, with pertuzumab suppressing HER2 heterodimerization and trastuzumab inducing antitumor immunity. However, in vivo evidence for this synergy is lacking. In this study, we found that the therapeutic efficacy elicited by their combination occurs through their joint ability to activate the classical complement pathway, resulting in both complement-dependent cytotoxicity and complement-dependent cellular phagocytosis of HER2+ tumors. We also demonstrate that tumor C1q expression is positively associated with survival outcome in HER2+ BC patients and that complement regulators CD55 and CD59 were inversely correlated with outcome, suggesting the clinical importance of complement activity. Accordingly, inhibition of C1q in mice abolished the synergistic therapeutic activity of T+P therapy, whereas knockdown of CD55 and CD59 expression enhanced T+P efficacy. In summary, our study identifies classical complement activation as a significant antitumor MOA for T+P therapy that may be functionally enhanced to potentially augment clinical therapeutic efficacy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.