Immune-infiltrated kidney organoid-on-chip model for assessing T cell bispecific antibodies

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 35; p. e2305322120
• Main Authors: Kroll, Katharina T, Mata, Mariana M, Homan, Kimberly A, Micallef, Virginie, Carpy, Alejandro, Hiratsuka, Ken, Morizane, Ryuji, Moisan, Annie, Gubler, Marcel, Walz, Antje-Christine, Marrer-Berger, Estelle, Lewis, Jennifer A
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.08.2023
• Subjects: Antibodies; Antibodies, Bispecific; Antigens; Biological Sciences; Bispecific antibodies; Cancer; Cancer immunotherapy; CD3 antigen; CD8 antigen; Cell activation; Histocompatibility antigen HLA; HLA-A2 Antigen; Human tissues; Humans; Immune system; Immunotherapy; Kidney; Kidneys; Leukocytes, Mononuclear; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Organoids; Peptides; Peripheral blood mononuclear cells; Physical Sciences; T cell receptors; Three dimensional flow; Three dimensional models; Tumors; Wilms' tumor; kidney organoids; immuno-oncology; T cell bispecific antibodies; organ-on-chip
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2305322120

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.