Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade

Geuijen, Cecile; Nardis, Camilla De; Maussang, David; Rovers, Eric; Gallenne, Tristan; Hendriks, Linda; Visser, Therèse; Nijhuis, Roy; Logtenberg, Ton; Kruif, John de; Gros, Piet; Throsby, Mark

doi:10.1016/j.ccell.2021.07.015

Cited by 10 publications

(13 citation statements)

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“…Zenocutuzumab, a bispecific monoclonal antibody that binds to HER 2 and HER 3 receptors and blocks the interaction of NRG1 fusion protein with its receptor HER3, has been shown to induce a response in tumors harboring NRG1 fusions in preclinical and early clinical studies. 97,98 A phase I/II trial evaluating zenocutuzumab in patients with various solid tumors harboring a NRG1 fusion is currently underway (ClinicalTrials. gov identifier: NCT02912949).…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Systemic therapy in metastatic pancreatic adenocarcinoma: current practice and perspectives

et al. 2021

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Major breakthroughs have been achieved in the management of metastatic pancreatic ductal adenocarcinoma (PDAC) with FOLFIRINOX (5-fluorouracil + irinotecan + oxaliplatin) and gemcitabine plus nab-paclitaxel approved as a first-line therapy, although the prognosis is still poor. At progression, patients who maintain a good performance status (PS) can benefit from second-line chemotherapy. To address the concern of achieving tumor control while maintaining a good quality of life, maintenance therapy is a concept that has now emerged. After a FOLFIRINOX induction treatment, maintenance with 5-fluorouracil (5-FU) seems to offer a promising approach. Although not confirmed in large, prospective trials, gemcitabine alone as a maintenance therapy following induction treatment with gemcitabine plus nab-paclitaxel could be an option, while a small subset of patients with a germline mutation of breast cancer gene ( BRCA) can benefit from the polyadenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib. The rate of PDAC with molecular alterations that could lead to a specific therapy is up to 25%. The Food and Drug Administration (FDA) recently approved larotrectinib for patients with any tumors harboring a neurotrophic tyrosine receptor kinase ( NTRK) gene fusion, and pembrolizumab for patients with a mismatch repair deficiency in a second-line setting, including PDAC. Research focused on targeted therapy and immunotherapy is active and could improve patients’ outcomes in the near future.

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Section: Parp Inhibitorsmentioning

confidence: 99%

Systemic therapy in metastatic pancreatic adenocarcinoma: current practice and perspectives

et al. 2021

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“…In a phase I study, it exhibited similar efficacy to trastuzumab combined with pertuzumab [121]. Dual targeting of EGFR + HER2, HER2 + HER3, or EGFR + cMET has been developed, and some of them have entered phase I clinical trials (Table 1) [121][122][123].…”

Section: Other Bispecific Antibodiesmentioning

confidence: 99%

“…As it is difficult to predict the function of the domain antibody format from parental full antibodies, high‐throughput screening such as phage/yeast/ Escherichia coli display systems have been adapted to aid the identification of functional multivalent antibody formats from several thousand candidates. For example, unbiased phenotypic screening of more than 500 bispecific IgG yielded a novel HER2‐HER3 bispecific IgG1 that reduced tumor volume in vivo by a “dock and block” mechanism that is not feasible with the two parental mAbs [123]. In addition to the antibody‐antigen interaction and antigen selection, it has been acknowledged that the multivalent domain antibody format impacts the function of multivalent domain antibodies.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Antibody variable region engineering for improving cancer immunotherapy

Lou

Cao

2022

Cancer Communications

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The efficacy and specificity of conventional monoclonal antibody (mAb) drugs in the clinic require further improvement. Currently, the development and application of novel antibody formats for improving cancer immunotherapy have attracted much attention. Variable region‐retaining antibody fragments, such as antigen‐binding fragment (Fab), single‐chain variable fragment (scFv), bispecific antibody, and bi/trispecific cell engagers, are engineered with humanization, multivalent antibody construction, affinity optimization and antibody masking for targeting tumor cells and killer cells to improve antibody‐based therapy potency, efficacy and specificity. In this review, we summarize the application of antibody variable region engineering and discuss the future direction of antibody engineering for improving cancer therapies.

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“…4,5,9,10 These chimeric NRG1 fusion proteins are considered clinically actionable oncogenic drivers via HER2/HER3 inhibition (Fig 1). 4,[11][12][13] Zenocutuzumab (Zeno, MCLA-128) is a bispecific humanized full-length immunoglobulin G1 antibody with enhanced antibody-dependent cellular cytotoxicity activity. It has a dual anticancer mechanism, docking on often abundantly expressed HER2, thereby positioning the antibody to block ligand binding to HER3, and preventing HER2-HER3 heterodimerization and downstream signaling.…”

Section: Introductionmentioning

confidence: 99%

“…Zeno potently inhibited ligand-driven tumor growth in preclinical studies in NRG1 fusion-positive (NRG1+) breast cancer models. 11 A prospective clinical validation of NRG1 fusions as actionable oncogenic drivers that may be amenable to targeted therapy is being performed with Zeno in the clinical phase I/II eNRGy study (ClinicalTrials.gov identifier: NCT02912949). Given the rarity of NRG1+ cancers, Zeno is also available through an early access program (ClinicalTrials.gov identifier: NCT04100694), which our patient accessed.…”

Section: Introductionmentioning

confidence: 99%