T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens,thereby engaging with CD3 on the T cell receptor.This linkage between tumor cells and T cells actively triggers T...T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens,thereby engaging with CD3 on the T cell receptor.This linkage between tumor cells and T cells actively triggers T cell activation and initiates targeted killing of the identified tumor cells.These antibodies have emerged as one of the most promising avenues within tumor immunotherapy.However,despite success in treating hematological malignancies,significant advancements in solid tumors have yet to be explored.In this review,we aim to address the critical challenges associated with T cellredirecting bispecific antibodies and explore novel strategies to overcome these obstacles,with the ultimate goal of expanding the application of this therapy to include solid tumors.展开更多
Bispecific antibodies(bsAbs)refer to a large family of molecules that recognize two different epitopes or antigens.Although a series of challenges,especially immunogenicity and chain mispairing issues,once hindered th...Bispecific antibodies(bsAbs)refer to a large family of molecules that recognize two different epitopes or antigens.Although a series of challenges,especially immunogenicity and chain mispairing issues,once hindered the development of bsAbs,they have been gradually overcome with the help of rapidly developing technologies in the past 5 decades.In the meantime,an increasing number of bsAb platforms have been designed to satisfy different clinical demands.Currently,numerous preclinical and clinical trials are underway,portraying a promising future for bsAb-based cancer treatment.Nevertheless,bsAb drugs still face enormous challenges in their application as cancer therapeutics,including tumor heterogeneity and mutational burden,intractable tumor microenvironment(TME),insufficient costimulatory signals to activate T cells,the necessity for continuous injection,fatal systemic side effects,and off-target toxicities to adjacent normal cells.Therefore,we provide several strategies as solutions to these issues,which comprise generating multispecific bsAbs,discovering neoantigens,combining bsAbs with other anticancer therapies,exploiting natural killer(NK)-cell-based bsAbs and producing bsAbs in situ.In this review,we mainly discuss previous and current challenges in bsAb development and underscore corresponding strategies,with a brief introduction of several typical bsAb formats.展开更多
tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense mutant.However,there are currently no approved targeted therapies or immunotherapies against mutant ...tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense mutant.However,there are currently no approved targeted therapies or immunotherapies against mutant p53.Here,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in vitro.We then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic effects.Our results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type p53.In cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular cytotoxicity.We made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 alleles.In vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in mice.The administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 antibody.These results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.展开更多
基金supported by the National Natural Science Foundation of China(Nos.32070940 and 81991491)the China Postdoctoral Science Foundation(No.2021M700115)+2 种基金the Postdoctoral Innovation Talents Support Program(No.BX20220189,China)the Science and Technology Planning Project of Fujian Province(No.2022L3080,China)the CAMS Innovation Fund for Medical Sciences(No.2019RU022,China).
文摘T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens,thereby engaging with CD3 on the T cell receptor.This linkage between tumor cells and T cells actively triggers T cell activation and initiates targeted killing of the identified tumor cells.These antibodies have emerged as one of the most promising avenues within tumor immunotherapy.However,despite success in treating hematological malignancies,significant advancements in solid tumors have yet to be explored.In this review,we aim to address the critical challenges associated with T cellredirecting bispecific antibodies and explore novel strategies to overcome these obstacles,with the ultimate goal of expanding the application of this therapy to include solid tumors.
文摘Bispecific antibodies(bsAbs)refer to a large family of molecules that recognize two different epitopes or antigens.Although a series of challenges,especially immunogenicity and chain mispairing issues,once hindered the development of bsAbs,they have been gradually overcome with the help of rapidly developing technologies in the past 5 decades.In the meantime,an increasing number of bsAb platforms have been designed to satisfy different clinical demands.Currently,numerous preclinical and clinical trials are underway,portraying a promising future for bsAb-based cancer treatment.Nevertheless,bsAb drugs still face enormous challenges in their application as cancer therapeutics,including tumor heterogeneity and mutational burden,intractable tumor microenvironment(TME),insufficient costimulatory signals to activate T cells,the necessity for continuous injection,fatal systemic side effects,and off-target toxicities to adjacent normal cells.Therefore,we provide several strategies as solutions to these issues,which comprise generating multispecific bsAbs,discovering neoantigens,combining bsAbs with other anticancer therapies,exploiting natural killer(NK)-cell-based bsAbs and producing bsAbs in situ.In this review,we mainly discuss previous and current challenges in bsAb development and underscore corresponding strategies,with a brief introduction of several typical bsAb formats.
基金supported by the Cancer Prevention and Research Institute of Texas(No.RR190043).
文摘tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense mutant.However,there are currently no approved targeted therapies or immunotherapies against mutant p53.Here,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in vitro.We then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic effects.Our results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type p53.In cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular cytotoxicity.We made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 alleles.In vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in mice.The administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 antibody.These results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.
