Dataset Information

Mitigating the risk of cytokine release syndrome in a Phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling.

ABSTRACT: Mosunetuzumab, a T-cell dependent bispecific antibody that binds CD3 and CD20 to drive T-cell mediated B-cell killing, is currently being tested in non-Hodgkin lymphoma. However, potent immune stimulation with T-cell directed therapies poses the risk of cytokine release syndrome, potentially limiting dose and utility. To understand mechanisms behind safety and efficacy and explore safety mitigation strategies, we developed a novel mechanistic model of immune and antitumor responses to the T-cell bispecifics (mosunetuzumab and blinatumomab), including the dynamics of B- and T-lymphocytes in circulation, lymphoid tissues, and tumor. The model was developed and validated using mosunetuzumab nonclinical and blinatumomab clinical data. Simulations delineated mechanisms contributing to observed cell and cytokine (IL6) dynamics and predicted that initial step-fractionated dosing limits systemic T-cell activation and cytokine release without compromising tumor response. These results supported a change to a step-fractionated treatment schedule of mosunetuzumab in the ongoing Phase I clinical trial, enabling safer administration of higher doses.

SUBMITTER: Hosseini I

PROVIDER: S-EPMC7455723 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Mitigating the risk of cytokine release syndrome in a Phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling.

Hosseini Iraj I Gadkar Kapil K Stefanich Eric E Li Chi-Chung CC Sun Liping L LL Chu Yu-Waye YW Ramanujan Saroja S

NPJ systems biology and applications 20200828 1

Mosunetuzumab, a T-cell dependent bispecific antibody that binds CD3 and CD20 to drive T-cell mediated B-cell killing, is currently being tested in non-Hodgkin lymphoma. However, potent immune stimulation with T-cell directed therapies poses the risk of cytokine release syndrome, potentially limiting dose and utility. To understand mechanisms behind safety and efficacy and explore safety mitigation strategies, we developed a novel mechanistic model of immune and antitumor responses to the T-cell ...[more]

PMID: 32859946

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Project description:B-cell lymphoma is a group of malignant proliferative diseases originating from lymphoid tissue with different clinical manifestations and biological characteristics. It can occur in any part of the body, accounting for more than 80% of all lymphomas. The present study aimed to construct bispecific single-domain antibodies against CD20 and CD3 and to evaluate their function in killing tumor cells in vitro. A Bactrian camel was immunized with a human CD20 extracellular peptide, and the VHH gene was cloned and ligated into a phagemid vector to construct the phage antibody display library. A phage antibody library with a size of 1.2 × 108 was successfully constructed, and the VHH gene insertion rate was 91.7%. Ninety-two individual clones were randomly picked and screened by phage ELISA. Six strains with the high binding ability to human CD20 were named 11, 30, 71, 72, 83, and 92, and induced expression and purification were performed to obtain soluble CD20 single-domain antibodies. The obtained single-domain antibodies could specifically bind to human CD20 polypeptide and cell surface-expressed CD20 molecules in ELISA, Western blot, and cell immunofluorescence assays. The anti-CD20/CD3 bispecific nanobody (BsNb) was successfully constructed by fusing the anti-CD20 VHH gene with the anti-CD3 VHH and the bispecific single-domain antibody was expressed, purified, and validated. Anti-CD20/CD3 BsNb can specifically bind CD20 molecules on the surface of human lymphoma Raji cells and CD3 molecules on the surface of T cells in flow cytometry analysis and effectively mediate peripheral blood mononuclear cells (PBMCs) target Raji cells with a killing efficiency of up to 30.4%, as measured by the lactate dehydrogenase (LDH) method. The release of hIFN-γ from PBMCs during incubation with anti-CD20/CD3 BsNb was significantly higher than that of the control group (p < 0.01). The anti-CD20/CD3 BsNb could maintain 80% binding activity after incubation with human serum at 37 °C for 48 h. These results indicated the strong antitumor effect of the constructed anti-CD20/CD3 BsNb and laid the foundation for the further development of antitumor agents and the clinical application of anti-CD20/CD3 BsNb.

Project description:Charge heterogeneity is an important quality attribute of therapeutic antibodies, and a detailed understanding of charge heterogeneity arising from post-translational modifications (PTMs) is required by regulatory agencies during drug development. Among antibody therapeutics, the bispecific antibody with two distinct Fab domains targeting distinct antigens provides additional complexity to the charge profile. In this study, charge variant species were enriched from three bispecific antibodies (bsAbs) each containing one anti-CD3 binding arm designed with differential affinity to CD3. The charge heterogeneity corresponding to each anti-CD3 arm within each enriched fraction was evaluated using a domain-specific, digestion-assisted imaged capillary isoelectric focusing (icIEF) method known as DiCE. Through fractionation, we observed that the anti-CD3 arm of each bispecific antibody exhibited different distributions of acidic variants, even when the anti-CD3 arms were identical based on primary sequence. Reduced peptide mapping was performed on specific fractions to identify unique site-specific PTMs that were uncovered or enriched through fractionation. In each case, the bispecific arm that was most susceptible to PTMs exhibited a more basic isoelectric point. Conformational stability analysis of each bispecific antibody using differential scanning calorimetry suggested that the more basic Fab arm tended to be correlated with a lower melting temperature, although it is unclear the extent to which PTMs on the basic arm may contribute to reduced conformational stability. Overall, these results provide additional evidence that each of the two arms of a bispecific antibody may exhibit differential susceptibility to post-translational modification and that this susceptibility is likely correlated with subtle differences in overall bispecific antibody structure, which is influenced by electrostatic properties inherent to the primary sequence. Future studies to obtain high-resolution structures of full-length bispecific antibodies by crystallography or cryo-electron microscopy may help to elucidate the driving force for susceptibility to PTMs in bispecific antibodies.

Dataset Information

Mitigating the risk of cytokine release syndrome in a Phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling.

Publications

Mitigating the risk of cytokine release syndrome in a Phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling.

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