Century Therapeutics announced that preclinical data from the Company?s iPSC-derived cell therapy platform was presented at the AACR Annual Meeting 2024. The posters highlight the Company?s end-to-end capabilities in iPSC reprogramming and differentiation, gene editing, synthetic biology, protein engineering and computational biology. The company presented new data advancing Allo-Evasion platform through the transgenic expression of HLA-G, which along with HLA-E can augment the protection against host natural killer cell-mediated rejection of iPSC derived cells also engineered to resist T cell recognition through the elimination of HLA-I and HLA-II expression.

This enhanced protection against rejection is designed to enable Century?s multi-dosing strategy that increases the period of drug exposure, potentially leading to deeper and more durable responses for patients in need. The company also presented new data describing novel, dual-targeting CAR for B cell mediated malignancies which demonstrated promising in vitro and in vivo cytotoxicity and resisting antigen loss, and which the company believes expands the potential of allogeneic CAR-T cell therapy beyond currently available options in oncology that only target CD19. Along with other important preclinical data presented at AACR, the findings to date highlight unique gene editing, protein engineering, and manufacturing capabilities that are the foundations of allogeneic cell therapy pipeline and platform.

The Discovery of a Novel CD19xCD22 Dual-Targeting CAR For the Development of an iPSC-Derived Cell Therapy: Through its industry leading engineering capabilities, Century has developed a CD19xCD22 bispecific, CD22 biparatopic chimeric antigen receptor (CAR), which was transduced into primary T cells and demonstrated cytotoxicity activity against CD19 and CD22-positive tumor cells, as well as CD19 knockout and CD22 knockout cell lines in vitro and in vivo mouse xenograft models. This novel CAR was engineered and tested in iPSC-derived gamma-delta T cells, showing in vitro tumor cell cytotoxicity. These findings support the continued examination of a CD19xCD22 bispecific CAR for off-the-shelf allogeneic cell therapy to expand patient access beyond CD19 CAR-T cell therapies.

Engineered Expression Of HLA-E And HLA-G Protects iPSC-Derived Cells from Killing by Primary NK Cells: In this study, the Company showed that the combination of HLA-E and HLA-G expression was the most effective in protecting allogeneic drug products from elimination of genetically dissimilar cells. Investigators assessed allo-evasion from natural killer (NK) cells by iPSC-derived cells engineered to express HLA-E and -G. NK cells across donors expressed heterogeneous combinations of HLA-E and -G ligands. K562 and iPSC-derived cells lacking HLA-I were susceptible to killing by PBMCs.

Overexpression of HLA-E and -G offered protection to K562 and iPSC-derived cells against all tested donors. HLA-E offered more protection than HLA-G, and the combination of both HLA-E and -G was most potent. When a genetically dissimilar HLA Class I protein family is deleted to prevent T cell mediated graft rejection, expression of the more-conserved HLA-E and -G can effectively protect allogeneic drug products from elimination.

The company believes this data further reinforces the Company?s proprietary Allo-Evasion? technology and its potential to evade identification by the host immune system, which would allow for repeat dosing without rejection, enabling increased persistence of the cells during the treatment period and potentially leading to deeper and more durable responses. Screening iPSC Lines for Optimal Characteristics of Differentiation into Immune Effector Cells for Clinical Programs: Century outlined the genomic characterization of both its clinical-grade PBMC-derived and its gamma-delta T cell-derived iPSC lines (PiPSCs and TiPSCs, respectively).

The Company successfully reprogrammed these cell lines from multiple donors and analyzed them through its genomic characterization pipeline and tiered them based on potential genetic liabilities to determine those best suited for clinical development. Multiple lines were then identified and iPSC and TiPSC were successfully differentiated to immune effector cells. d35 iT cells exhibited diverse phenotypes, yields, and function.

These lines can then be specialized into effector cells exhibiting heightened functionality, applicable to conditions including autoimmune disorders and oncology indications, among others. Once differentiated, Century further screened the lines for their in vitro cytotoxicity and post target-engagement persistence, thereby discovering those that were most suitable for further clinical development. Discovery of a Novel NECTIN4 iPSC-derived Cell Therapy for the Treatment of Solid Tumors: Century is developing an iPSC-derived cell therapy targeting NECTIN4, an established biomarker linked to carcinogenesis, worse prognosis, and disease severity, for the treatment of NECTIN4 expressing solid tumors.

In these preclinical studies, Century identified novel single-domain antibodies (VHH) that bind to multiple epitopes on the NECTIN4 extracellular domain. The VHH antibodies were engineered into CAR formats and characterized for expression, cell activation through antigen engagement, and cytotoxicity activity in primary T cells. Selected binders demonstrated efficacy in multiple CAR formats in primary T cells in a mouse xenograft model using OVCar-3 tumor cells.

The lead CARs engineered into primary T cells demonstrated tumor inhibition similar to a reference CAR using the ASG-5ME antibody (Enfortumab) as the NECTIN4 binder. The CARs were engineered into Century?s iPSC-derived iNK and iT cells and demonstrated cytotoxicity activity against a panel of cell lines with a range of cell surface expression of NECTIN4. The company believes these findings support the advancement of Century?s lead NECTIN4 binder for the development of an iPSC-derived cell therapy to treat NECTIN4 positive solid tumors.