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Unlocking the potential of agonist antibodies for treating cancer using antibody engineering.

ABSTRACT: Agonist antibodies that target immune checkpoints, such as those in the tumor necrosis factor receptor (TNFR) superfamily, are an important class of emerging therapeutics due to their ability to regulate immune cell activity, especially for treating cancer. Despite their potential, to date, they have shown limited clinical utility and further antibody optimization is urgently needed to improve their therapeutic potential. Here, we discuss key antibody engineering approaches for improving the activity of antibody agonists by optimizing their valency, specificity for different receptors (e.g., bispecific antibodies) and epitopes (e.g., biepitopic or biparatopic antibodies), and Fc affinity for Fcγ receptors (FcγRs). These powerful approaches are being used to develop the next generation of cancer immunotherapeutics with improved efficacy and safety.

SUBMITTER: Jhajj HS

PROVIDER: S-EPMC9742327 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Unlocking the potential of agonist antibodies for treating cancer using antibody engineering.

Jhajj Harkamal S HS Lwo Timon S TS Yao Emily L EL Tessier Peter M PM

Trends in molecular medicine 20221104 1

Agonist antibodies that target immune checkpoints, such as those in the tumor necrosis factor receptor (TNFR) superfamily, are an important class of emerging therapeutics due to their ability to regulate immune cell activity, especially for treating cancer. Despite their potential, to date, they have shown limited clinical utility and further antibody optimization is urgently needed to improve their therapeutic potential. Here, we discuss key antibody engineering approaches for improving the act ...[more]

PMID: 36344331

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Project description:BackgroundThrombocytopenia is a common complication in cancer patients undergoing chemotherapy. Chemotherapy-induced thrombocytopenia (CIT) leads to dose reduction and treatment delays, lowering chemotherapy efficacy and survival rate. Thus, rapid recovery and continuous maintenance of platelet count during chemotherapy cycles are crucial in patients with CIT. Thrombopoietin (TPO) and its receptor, myeloid proliferative leukemia (MPL) protein, play a major role in platelet production. Although several MPL agonists have been developed to regulate thrombopoiesis, none have been approved for the management of CIT due to concerns regarding efficacy or safety. Therefore, the development of effective MPL agonists for treating CIT needs to be further expanded.MethodsAnti-MPL antibodies were selected from the human combinatorial antibody phage libraries using phage display. We identified 2R13 as the most active clone among the binding antibodies via cell proliferation assay using BaF3/MPL cells. The effect of 2R13 on megakaryocyte differentiation was evaluated in peripheral blood CD34+ cells by analyzing megakaryocyte-specific differentiation markers (CD41a+ and CD42b+) and DNA ploidy using flow cytometry. The 2R13-induced platelet production was examined in 8- to 10-week-old wild-type BALB/c female mice and a thrombocytopenia mouse model established by intraperitoneal injection of 5-fluorouracil (150 mg/kg). The platelet counts were monitored twice a week over 14 days post-initiation of treatment with a single injection of 2R13, or recombinant human TPO (rhTPO) for seven consecutive days.ResultsWe found that 2R13 specifically interacted with MPL and activated its signaling pathways. 2R13 stimulated megakaryocyte differentiation, evidenced by increasing the proportion of high-ploidy (≥ 8N) megakaryocytes in peripheral blood-CD34+ cells. The platelet count was increased by a single injection of 2R13 for up to 14 days. Injection of 5-fluorouracil considerably reduced the platelet count by day 4, which was recovered by 2R13. The platelets produced by 2R13 sustained a higher count than that achieved using seven consecutive injections of rhTPO.ConclusionsOur findings suggest that 2R13 is a promising therapeutic agent for CIT treatment.

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Unlocking the potential of agonist antibodies for treating cancer using antibody engineering.

Publications

Unlocking the potential of agonist antibodies for treating cancer using antibody engineering.

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