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Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies

ABSTRACT: We performed bulk RNAsequencing of neutrophils isolated from whole blood treated with CD20-TCB to study the early kinetics of cytokine release in neutrophils.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234673 | GEO | 2023/06/17

REPOSITORIES: GEO

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Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies

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Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies

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Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies

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Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies

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Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies

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Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies.

Project description:T-cell-recruiting bispecific antibodies (T-BsAbs) have shown potent tumor killing activity in humans, but cytokine release-related toxicities have affected their clinical utility. The use of novel anti-CD3 binding domains with more favorable properties could aid in the creation of T-BsAbs with improved therapeutic windows. Using a sequence-based discovery platform, we identified new anti-CD3 antibodies from humanized rats that bind to multiple epitopes and elicit varying levels of T-cell activation. In T-BsAb format, 12 different anti-CD3 arms induce equivalent levels of tumor cell lysis by primary T-cells, but potency varies by a thousand-fold. Our lead CD3-targeting arm stimulates very low levels of cytokine release, but drives robust tumor antigen-specific killing in vitro and in a mouse xenograft model. This new CD3-targeting antibody underpins a next-generation T-BsAb platform in which potent cytotoxicity is uncoupled from high levels of cytokine release, which may lead to a wider therapeutic window in the clinic.

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Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release.

Project description:BackgroundT cell-based immunotherapies using chimeric antigen receptors (CAR) or bispecific antibodies (BsAb) have produced impressive responses in hematological malignancies. However, major hurdles remained, including cytokine release syndrome, neurotoxicity, on-target off-tumor effects, reliance on autologous T cells, and failure in most solid tumors. BsAb armed T cells offer a safe alternative.MethodsWe generated ex vivo armed T cells (EATs) using IgG-[L]-scFv-platformed BsAb, where the anti-CD3 (huOKT3) scFv was attached to the light chain of a tumor-binding IgG. BsAb density on EAT, in vitro cytotoxicity, cytokine release, in vivo trafficking into tumors, and their antitumor activities were evaluated in multiple cancer cell lines and patient-derived xenograft mouse models. The efficacy of EATs after cryopreservation was studied, and gamma delta (γδ) T cells were investigated as unrelated alternative effector T cells.ResultsThe antitumor potency of BsAb armed T cells was substantially improved using the IgG-[L]-scFv BsAb platform. When compared with separate BsAb and T cell injection, EATs released less TNF-α, and infiltrated tumors faster, while achieving robust antitumor responses. The in vivo potency of EAT therapy depended on BsAb dose for arming, EAT cell number per injection, total number of EAT doses, and treatment schedule intensity. The antitumor efficacy of EATs was preserved following cryopreservation, and EATs using γδ T cells were safe and as effective as αβ T cell-EATs.ConclusionsEATs exerted potent antitumor activities against a broad spectrum of human cancer targets with remarkable safety. The antitumor potency of EATs depended on BsAb dose, cell number and total dose, and schedule. EATs were equally effective after cryopreservation, and the feasibility of third-party γδ-EATs offered an alternative for autologous T cell sources.

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Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning.

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Dissecting the molecular basis of high viscosity of monospecific and bispecific IgG antibodies.

Project description:Some antibodies exhibit elevated viscosity at high concentrations, making them poorly suited for therapeutic applications requiring administration by injection such as subcutaneous or ocular delivery. Here we studied an anti-IL-13/IL-17 bispecific IgG4 antibody, which has anomalously high viscosity compared to its parent monospecific antibodies. The viscosity of the bispecific IgG4 in solution was decreased by only ~30% in the presence of NaCl, suggesting electrostatic interactions are insufficient to fully explain the drivers of viscosity. Intriguingly, addition of arginine-HCl reduced the viscosity of the bispecific IgG4 by ~50% to its parent IgG level. These data suggest that beyond electrostatics, additional types of interactions such as cation-π and/or π-π may contribute to high viscosity more significantly than previously understood. Molecular dynamics simulations of antibody fragments in the mixed solution of free arginine and explicit water were conducted to identify hotspots involved in self-interactions. Exposed surface aromatic amino acids displayed an increased number of contacts with arginine. Mutagenesis of the majority of aromatic residues pinpointed by molecular dynamics simulations effectively decreased the solution's viscosity when tested experimentally. This mutational method to reduce the viscosity of a bispecific antibody was extended to a monospecific anti-GCGR IgG1 antibody with elevated viscosity. In all cases, point mutants were readily identified that both reduced viscosity and retained antigen-binding affinity. These studies demonstrate a new approach to mitigate high viscosity of some antibodies by mutagenesis of surface-exposed aromatic residues on complementarity-determining regions that may facilitate some clinical applications.

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Tocilizumab: The Key to Stop Coronavirus Disease 2019 (COVID-19)-Induced Cytokine Release Syndrome (CRS)?

Project description:The COVID-19 disease is an unprecedented international public health emergency and considerably impacts the global economy and health service system. While awaiting the development of an effective vaccine, searching for the therapy for severe or critical COVID-19 patients is essential for reducing the mortality and alleviating the tension of the health service system. Cytokine release syndrome (CRS) induced by elevated interleukin-6 was recognized to underscore the pathology of severe COVID-19 patients. Inhibiting CRS by agents suppressing IL-6 may relieve symptoms, shorten the hospital stay and reduce the need for oxygen therapy. Although evidence from randomized, double-blinded clinical trials is still lacking, the IL-6R inhibitor tocilizumab (TCZ) has shown some clinical benefits in the treatment of severe COVID-19 patients and have been included in clinical guidelines. In this review, we focused on the possible mechanisms of TCZ in the treatment of CRS and highlighted some significant considerations in the use of TCZ to treat COVID-19 patients.

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