By binding to multiple antigens simultaneously,multispecific antibodies are expected to substantially improve both the activity and long-term efficacy of antibody-based immunotherapy.Immune cell engagers,a subclass of...By binding to multiple antigens simultaneously,multispecific antibodies are expected to substantially improve both the activity and long-term efficacy of antibody-based immunotherapy.Immune cell engagers,a subclass of antibody-based constructs,consist of engineered structures designed to bridge immune effector cells to their target,thereby redirecting the immune response toward the tumor cells or infected cells.The increasing number of recent clinical trials evaluating immune cell engagers reflects the important role of these molecules in new therapeutic approaches for cancer and infections.In this review,we discuss how different immune cell types(T and natural killer lymphocytes,as well as myeloid cells)can be bound by immune cell engagers in immunotherapy for cancer and infectious diseases.Furthermore,we explore the preclinical and clinical advancements of these constructs,and we discuss the challenges in translating the current knowledge from cancer to the virology field.Finally,we speculate on the promising future directions that immune cell engagers may take in cancer treatment and antiviral therapy.展开更多
Advancements in protein engineering have driven the continuous optimization of T-cell engagers(TCEs),resulting in remarkable clinical outcomes in the treatment of B-cell malignancies.Moreover,developing tri-or multisp...Advancements in protein engineering have driven the continuous optimization of T-cell engagers(TCEs),resulting in remarkable clinical outcomes in the treatment of B-cell malignancies.Moreover,developing tri-or multispecific TCEs has emerged as a promising strategy to address the challenges of tumor heterogeneity and antigen escape.However,considerable obstacles remain,primarily in format design.In this study,we engineered BAFF-based TCEs with various formats that incorporate anti-CD3 Fab or IgG domains fused with BAFF ligands to target BAFF recep tors(BAFFR,BCMA,and TACI).These constructs varied in valency and the presence or absence of long-acting ele ments such as Fc domains or the albumin binding domain consensus sequence(ABDCon).Although the inclusion of an Fc domain did not enhance sustained tumor eradication,variations in valency and spatial configuration profoundly influenced cytotoxicity.We identified TriBAFF/CD3/ABDCon as the optimal trifunctional construct,fea turing an anti-CD3 Fab backbone with BAFF and ABDCon fused to the C-termini of the heavy and light chains.This design facilitates optimal immune synapse formation between the target cells and T cells and effectively controls tumor burdens in various B-cell malignancy models with good tolerability.Notably,TriBAFF/CD3/ABDCon outper formed conventional therapies,including blinatumomab and BAFF-based CAR-T cells,in models of heterogeneous leukemia and aggressive lymphoma.These findings underscore the potential of using natural ligands as antibody-targeting modules and provide valuable insights into the design of the next generation of multispecific TCEs,which hold promise for improving treatment outcomes in a wide range of malignancies and beyond.展开更多
基金CR is supported by a grant from the National Research Fund Luxembourg(FNR),Doctoral Training Unit"i2TRON",PRIDE19/14254520,project 20200831.
文摘By binding to multiple antigens simultaneously,multispecific antibodies are expected to substantially improve both the activity and long-term efficacy of antibody-based immunotherapy.Immune cell engagers,a subclass of antibody-based constructs,consist of engineered structures designed to bridge immune effector cells to their target,thereby redirecting the immune response toward the tumor cells or infected cells.The increasing number of recent clinical trials evaluating immune cell engagers reflects the important role of these molecules in new therapeutic approaches for cancer and infections.In this review,we discuss how different immune cell types(T and natural killer lymphocytes,as well as myeloid cells)can be bound by immune cell engagers in immunotherapy for cancer and infectious diseases.Furthermore,we explore the preclinical and clinical advancements of these constructs,and we discuss the challenges in translating the current knowledge from cancer to the virology field.Finally,we speculate on the promising future directions that immune cell engagers may take in cancer treatment and antiviral therapy.
基金supported by Shenzhen Medical Research Fund(B2402027)the National Natural Science Foundation of China(32171464)+3 种基金Shenzhen Fundamental Research Program(Natural Science Foundation)-Key Basic Research Project(JCYJ20241202125200001)the National Key R&D Program of China(2019YFA0904200 and 2019YFA0906100)Shenzhen Nanshan District Health System Science and Technology Major Project(NSZD2023018)This study is a Nanshan District medical key discipline construction financial support project.
文摘Advancements in protein engineering have driven the continuous optimization of T-cell engagers(TCEs),resulting in remarkable clinical outcomes in the treatment of B-cell malignancies.Moreover,developing tri-or multispecific TCEs has emerged as a promising strategy to address the challenges of tumor heterogeneity and antigen escape.However,considerable obstacles remain,primarily in format design.In this study,we engineered BAFF-based TCEs with various formats that incorporate anti-CD3 Fab or IgG domains fused with BAFF ligands to target BAFF recep tors(BAFFR,BCMA,and TACI).These constructs varied in valency and the presence or absence of long-acting ele ments such as Fc domains or the albumin binding domain consensus sequence(ABDCon).Although the inclusion of an Fc domain did not enhance sustained tumor eradication,variations in valency and spatial configuration profoundly influenced cytotoxicity.We identified TriBAFF/CD3/ABDCon as the optimal trifunctional construct,fea turing an anti-CD3 Fab backbone with BAFF and ABDCon fused to the C-termini of the heavy and light chains.This design facilitates optimal immune synapse formation between the target cells and T cells and effectively controls tumor burdens in various B-cell malignancy models with good tolerability.Notably,TriBAFF/CD3/ABDCon outper formed conventional therapies,including blinatumomab and BAFF-based CAR-T cells,in models of heterogeneous leukemia and aggressive lymphoma.These findings underscore the potential of using natural ligands as antibody-targeting modules and provide valuable insights into the design of the next generation of multispecific TCEs,which hold promise for improving treatment outcomes in a wide range of malignancies and beyond.
