ABSTRACT
Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement.
Subject(s)
Antibodies, Bispecific , Antineoplastic Agents , Breast Neoplasms , Humans , Female , Xenograft Model Antitumor Assays , Cell Line, Tumor , Trastuzumab/pharmacology , Trastuzumab/therapeutic use , Receptor, ErbB-2/metabolism , Antibody-Dependent Cell Cytotoxicity , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapyABSTRACT
BACKGROUND: Standard dose (≤ 1 g) tranexamic acid (TXA) has established mortality benefit in trauma patients. The role of high dose IV TXA (≥2 g or ≥30 mg/kg as a single bolus) has been evaluated in the surgical setting, however, it has not been studied in trauma. We reviewed the available evidence of high dose IV TXA in any setting with the goal of informing its use in the adult trauma population. METHODS: We searched MEDLINE, EMBASE and unpublished sources from inception until July 27, 2022 for studies that compared standard dose with high dose IV TXA in adults (≥ 16 years of age) with hemorrhage. Screening and data abstraction was done independently and in duplicate. We pooled trial data using a random effects model and considered randomized controlled trials (RCTs) and observational cohort studies separately. We assessed the individual study risk of bias using the Cochrane Risk of Bias for RCTs and the Newcastle-Ottawa Scale for observational cohort studies. The overall certainty of evidence was assessed using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: We included 20 studies with a combined total of 12,523 patients. Based on pooled RCT data, and as compared to standard dose TXA, high dose IV TXA probably decreases transfusion requirements (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.76 to 0.97, moderate certainty) but with possibly no effect on blood loss (mean difference [MD] 43.31 ml less, 95% CI 135.53 to 48.90 ml less, low certainty), and an uncertain effect on thromboembolic events (OR 1.33, 95% CI 0.86 to 2.04, very low certainty) and mortality (OR 0.70, 95% CI 0.37 to 1.32, very low certainty). CONCLUSION: When compared to standard dose, high dose IV TXA probably reduces transfusion requirements with an uncertain effect on thromboembolic events and mortality. LEVEL OF EVIDENCE: Systematic review and meta-analysis, level IV.
