Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in ...Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells,with minimal expression observed in non-neoplastic tissues.We have developed a humanized monoclonal antibody,DUNP19,that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding.In multiple subcutaneous and orthotopic tumor xenograft mouse models,Lutetium-177 labeled DUNP19([^(177)Lu]Lu-DUNP19)enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts,effectively halting tumor progression and prolonging survival with minimal toxicity.Transcriptomic analyses of[^(177)Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms,including a previously reported TGF β-induced LRRC15+signature associated with immunotherapy resistance.In a syngeneic tumor model,administration of[^(177)Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy,yielding durable complete responses.Together,these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis,eradication,and reprogramming of LRRC15+tumor tissue that drives immunoresistance and disease aggressiveness in a wide range of currently untreatable malignancies.展开更多
基金supported in part by the Outsmarting Osteosarcoma Hero Award(Because of Sydney)the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Rose Hill Foundation Innovator Award+23 种基金supported by NCI R01CA201035,R01CA240711,R01CA229893DoD W81XWH-18-1-0223UCLA SPORE in Prostate Cancer(P50 CA092131)JCCC Cancer support grant from NIH P30 CA016042(PI:Teitell)Knut and Alice Wallenberg FoundationBertha Kamprad FoundationDavid H.Koch Prostate Cancer Foundation Young Investigator AwardSwedish Research CouncilSwedish Cancer SocietySIPEA FoundationSwedish Childhood Cancer FoundationJohn and Augusta Perssons FoundationRoyal Physiographic Society of LundFranke and Margareta Bergqvist FoundationCrafoord FoundationLund University Medical Faculty research time allocation award,IngaBrittArne Lundberg Research Foundation,the German Research Foundation(552440240)the German Cancer Consortium(DKTK)the German Federal Ministry of Education and Research(BMBFgrant no.01KD2206A/SATURN3)funding support from the Children’s Discovery Institute of the St.Louis Children’s Hospital.Confocal laser scanning microscopy was performed at the Advanced Light Microscopy/Spectroscopy Laboratory(RRID:SCR_022789)the Leica Microsystems Center of Excellence at the California NanoSystems Institute at UCLA with funding support from NIH Shared Instrumentation Grant S10OD025017Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center(JCCC)Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards P30 CA016042 and 5P30 AI028697。
文摘Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells,with minimal expression observed in non-neoplastic tissues.We have developed a humanized monoclonal antibody,DUNP19,that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding.In multiple subcutaneous and orthotopic tumor xenograft mouse models,Lutetium-177 labeled DUNP19([^(177)Lu]Lu-DUNP19)enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts,effectively halting tumor progression and prolonging survival with minimal toxicity.Transcriptomic analyses of[^(177)Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms,including a previously reported TGF β-induced LRRC15+signature associated with immunotherapy resistance.In a syngeneic tumor model,administration of[^(177)Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy,yielding durable complete responses.Together,these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis,eradication,and reprogramming of LRRC15+tumor tissue that drives immunoresistance and disease aggressiveness in a wide range of currently untreatable malignancies.
