PMID- 37603766 OWN - NLM STAT- MEDLINE DCOM- 20230823 LR - 20240222 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 120 IP - 35 DP - 2023 Aug 29 TI - Immune-infiltrated kidney organoid-on-chip model for assessing T cell bispecific antibodies. PG - e2305322120 LID - 10.1073/pnas.2305322120 [doi] LID - e2305322120 AB - T cell bispecific antibodies (TCBs) are the focus of intense development for cancer immunotherapy. Recently, peptide-MHC (major histocompatibility complex)-targeted TCBs have emerged as a new class of biotherapeutics with improved specificity. These TCBs simultaneously bind to target peptides presented by the polymorphic, species-specific MHC encoded by the human leukocyte antigen (HLA) allele present on target cells and to the CD3 coreceptor expressed by human T lymphocytes. Unfortunately, traditional models for assessing their effects on human tissues often lack predictive capability, particularly for "on-target, off-tumor" interactions. Here, we report an immune-infiltrated, kidney organoid-on-chip model in which peripheral blood mononuclear cells (PBMCs) along with nontargeting (control) or targeting TCB-based tool compounds are circulated under flow. The target consists of the RMF peptide derived from the intracellular tumor antigen Wilms' tumor 1 (WT1) presented on HLA-A2 via a bivalent T cell receptor-like binding domain. Using our model, we measured TCB-mediated CD8(+) T cell activation and killing of RMF-HLA-A2-presenting cells in the presence of PBMCs and multiple tool compounds. DP47, a non-pMHC-targeting TCB that only binds to CD3 (negative control), does not promote T cell activation and killing. Conversely, the nonspecific ESK1-like TCB (positive control) promotes CD8(+) T cell expansion accompanied by dose-dependent T cell-mediated killing of multiple cell types, while WT1-TCB* recognizing the RMF-HLA-A2 complex with high specificity, leads solely to selective killing of WT1-expressing cells within kidney organoids under flow. Our 3D kidney organoid model offers a platform for preclinical testing of cancer immunotherapies and investigating tissue-immune system interactions. FAU - Kroll, Katharina T AU - Kroll KT AD - Harvard University, School of Engineering and Applied Sciences, Cambridge, MA 02138. AD - Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115. FAU - Mata, Mariana M AU - Mata MM AD - Harvard University, School of Engineering and Applied Sciences, Cambridge, MA 02138. AD - Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115. FAU - Homan, Kimberly A AU - Homan KA AD - Harvard University, School of Engineering and Applied Sciences, Cambridge, MA 02138. AD - Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115. AD - Complex in vitro Systems, Safety Assessment, Genentech Inc., South San Francisco, CA 94080. FAU - Micallef, Virginie AU - Micallef V AD - Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel CH-4070, Switzerland. FAU - Carpy, Alejandro AU - Carpy A AD - Roche Pharma Research and Early Development, Roche Innovation Center Munich, Munich DE-82377, Germany. FAU - Hiratsuka, Ken AU - Hiratsuka K AD - Department of Medicine, Harvard Medical School, Boston, MA 02115. AD - Harvard Stem Cell Institute, Cambridge, MA 02138. FAU - Morizane, Ryuji AU - Morizane R AD - Department of Medicine, Harvard Medical School, Boston, MA 02115. AD - Harvard Stem Cell Institute, Cambridge, MA 02138. FAU - Moisan, Annie AU - Moisan A AD - Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel CH-4070, Switzerland. FAU - Gubler, Marcel AU - Gubler M AD - Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel CH-4070, Switzerland. FAU - Walz, Antje-Christine AU - Walz AC AD - Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel CH-4070, Switzerland. FAU - Marrer-Berger, Estelle AU - Marrer-Berger E AD - Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel CH-4070, Switzerland. FAU - Lewis, Jennifer A AU - Lewis JA AUID- ORCID: 0000-0002-0280-2774 AD - Harvard University, School of Engineering and Applied Sciences, Cambridge, MA 02138. AD - Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115. LA - eng GR - DP2 DK133821/DK/NIDDK NIH HHS/United States GR - UC2 DK126023/DK/NIDDK NIH HHS/United States GR - UG3 TR002155/TR/NCATS NIH HHS/United States GR - UH3 TR002155/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230821 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Antibodies, Bispecific) RN - 0 (HLA-A2 Antigen) SB - IM MH - Humans MH - *Antibodies, Bispecific MH - HLA-A2 Antigen MH - Leukocytes, Mononuclear MH - Kidney MH - Organoids PMC - PMC10467620 OTO - NOTNLM OT - T cell bispecific antibodies OT - immuno-oncology OT - kidney organoids OT - organ-on-chip COIS- Trestle Biotherapeutics was not involved in this research but has licensed research in engineering kidney tissue for therapeutic use from Harvard University. R.M. and J.A.L. are members of the Trestle Biotherapeutics Scientific Advisory Board and received stock options. V.M., A.C., and M.G. are employed by Hoffmann-La Roche, Ltd. K.A.H. is currently employed by Genentech, but carried out this work as a postdoctoral researcher in the lab of J.A.L. A patent was filed on the vascularized kidney organoid-on-chip model, which was licensed by Harvard University to Trestle Biotherapeutics (startup company in San Diego, CA). EDAT- 2023/08/21 18:41 MHDA- 2023/08/23 06:42 PMCR- 2024/02/21 CRDT- 2023/08/21 15:13 PHST- 2023/08/23 06:42 [medline] PHST- 2023/08/21 18:41 [pubmed] PHST- 2023/08/21 15:13 [entrez] PHST- 2024/02/21 00:00 [pmc-release] AID - 202305322 [pii] AID - 10.1073/pnas.2305322120 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2023 Aug 29;120(35):e2305322120. doi: 10.1073/pnas.2305322120. Epub 2023 Aug 21.