Dataset Information

Time-to-Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine-Citrulline-Monomethylauristatin E Antibody-Drug Conjugates.

ABSTRACT: Peripheral neuropathy (PN) is a common long-term debilitating toxicity of antimicrotubule agents. PN was the most frequent adverse event resulting in dose modifications and/or discontinuation of treatment for valine-citrulline-monomethylauristatin E antibody-drug conjugates (ADCs) developed at Genentech. A pooled time-to-event analysis across eight ADCs (~700 patients) was performed to evaluate the relationship between the ADC exposure and the risk for developing a clinically significant (grade ? 2) PN. In addition, the impact of demographic and pathophysiological risk factors on the risk for PN was explored. The time-to-event analysis suggested that the development of PN risk increased with ADC exposure, treatment duration, body weight, and previously reported PN. This model can be used to inform clinical strategies such as adaptations to dosing regimen and/or treatment duration as well as inform clinical eligibility to reduce the incidence of grade ? 2 PN.

SUBMITTER: Kagedal M

PROVIDER: S-EPMC6709423 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Time-to-Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine-Citrulline-Monomethylauristatin E Antibody-Drug Conjugates.

Kågedal Matts M Samineni Divya D Gillespie William R WR Lu Dan D Fine Bernard M BM Girish Sandhya S Li Chunze C Jin Jin Y JY

CPT: pharmacometrics & systems pharmacology 20190710 8

Peripheral neuropathy (PN) is a common long-term debilitating toxicity of antimicrotubule agents. PN was the most frequent adverse event resulting in dose modifications and/or discontinuation of treatment for valine-citrulline-monomethylauristatin E antibody-drug conjugates (ADCs) developed at Genentech. A pooled time-to-event analysis across eight ADCs (~700 patients) was performed to evaluate the relationship between the ADC exposure and the risk for developing a clinically significant (grade ...[more]

PMID: 31207190

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Project description:Simple Summary Chemotherapy-induced peripheral neuropathy (CIPN) remains a clinical challenge with a considerable impact on the effective treatment of cancers and quality of life during and after concluding chemotherapy. Given the limited understanding of CIPN, there are no options for the treatment and prevention of CIPN. Decades of research with the unsuccessful translation of preclinical findings to clinical studies argue for the requirement of human model systems. This review focuses on the translational potential of human induced pluripotent stem cells (iPSCs) in CIPN research. We provide an overview of the current studies and discuss important aspects to improve the translation of in vitro findings. We identified distinct effects on the neurite network and cell viability upon exposure to different classes of chemotherapy. Our study revealed considerable variability between donors and between neurons of the central and peripheral nervous system. Translational success may be improved by including multiple iPSC donors with known clinical data and selecting clinically relevant concentrations. Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially serious adverse effect of a wide range of chemotherapeutics. The lack of understanding of the molecular mechanisms underlying CIPN limits the efficacy of chemotherapy and development of therapeutics for treatment and prevention of CIPN. Human induced pluripotent stem cells (iPSCs) have become an important tool to generate the cell types associated with CIPN symptoms in cancer patients. We reviewed the literature for iPSC-derived models that assessed neurotoxicity among chemotherapeutics associated with CIPN. Furthermore, we discuss the gaps in our current knowledge and provide guidance for selecting clinically relevant concentrations of chemotherapy for in vitro studies. Studies in iPSC-derived neurons revealed differential sensitivity towards mechanistically diverse chemotherapeutics associated with CIPN. Additionally, the sensitivity to chemotherapy was determined by donor background and whether the neurons had a central or peripheral nervous system identity. We propose to utilize clinically relevant concentrations that reflect the free, unbound fraction of chemotherapeutics in plasma in future studies. In conclusion, iPSC-derived sensory neurons are a valuable model to assess CIPN; however, studies in Schwann cells and motor neurons are warranted. The inclusion of multiple iPSC donors and concentrations of chemotherapy known to be achievable in patients can potentially improve translational success.

Project description:The XpressCF+® cell-free protein synthesis system is a robust platform for the production of non-natural amino acids containing antibodies, which enable the site-specific conjugation of homogeneous antibody drug conjugates (ADCs) via click chemistry. Here, we present a robust and scalable means of achieving a 50-100% increase in IgG titers by combining the high productivity of cell-based protein synthesis with the unique ability of XpressCF+® reactions to produce correctly folded and assembled IgGs containing multiple non-natural amino acids at defined positions. This hybrid technology involves the pre-expression of an IgG light-chain (LC) protein in a conventional recombinant E. coli expression system, engineered to have an oxidizing cytoplasm. The prefabricated LC subunit is then added as a reagent to the cell-free protein synthesis reaction. Prefabricated LC increases IgG titers primarily by reducing the protein synthesis burden per IgG since the cell free translation machinery is only responsible for synthesizing the HC protein. Titer increases were demonstrated in four IgG products in scales ranging from 100-µL microplate reactions to 0.25-L stirred tank bioreactors. Similar titer increases with prefabricated LC were also demonstrated for a bispecific antibody in the scFvFc-FabFc format, demonstrating the generality of this approach. Prefabricated LC also increases robustness in cell-free reactions since it eliminates the need to fine-tune the HC-to-LC plasmid ratio, a critical parameter influencing IgG assembly and quality when the two IgG subunits are co-expressed in a single reaction. ADCs produced using prefabricated LC were shown to be identical to IgGs produced in cell-free alone by comparing product quality, in vitro cell killing, and FcRn receptor binding assays. This approach represents a significant step towards improving IgG titers and the robustness of cell-free protein synthesis reactions by integrating in vivo and in vitro protein production platforms.

Dataset Information

Time-to-Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine-Citrulline-Monomethylauristatin E Antibody-Drug Conjugates.

Publications

Time-to-Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine-Citrulline-Monomethylauristatin E Antibody-Drug Conjugates.

Similar Datasets

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