AP1903 is a bivalent "dimerizer" compound that binds FKBP and induces Fas cross-linking[1]. AP1903 rapidly induces dimerization and activation of iC9, inducing apoptosis of the gene modified T cells[2]. AP1903 has been widely used to inhibit tumor growth and increase circulating inflammatory cytokine/chemokine levels[3].
In vitro, AP1903 treatment for 24 hours significantly inhibited the viability of H1 cells transfected with iC9 gene, with an IC50 value of 0.1242±0.0083nM[4]. Treatment with 100nM AP1903 for 15 days significantly promoted the expansion of MFM (MSCVF36Vmpl) retroviral vector transduced cord blood cells[5]. Treatment with 50nM AP1903 for 5 days caused morphological changes in SH-SY5Y cells transfected with pIRES2-iC9 vector and induced cell differentiation[6].
In vivo, AP1903 treatment via a single intraperitoneal injection at a dose of 5mg/kg for 9 days ameliorated colitis symptoms and improved survival in acute colitis mice infused with WJ-MSCiCasp9+/Luc+ cells[7]. Intravenous injection of AP1903 (5mg/kg/day for 5 days) immediately after intravenous injection of EF1α-iCasp9-hΔCD19 murine induced pluripotent stem cells (miPSCs) resulted in delayed teratoma growth in mice[8].
References:
[1] Thomis D C, Marktel S, Bonini C, et al. A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease[J]. Blood, The Journal of the American Society of Hematology, 2001, 97(5): 1249-1257
[2] Elkeky R, Jacobsohn D A, Agarwal R, et al. Administration of rimiducid following haploidentical BPX-501 cells in children with malignant or non-malignant disorders who develop graft-versus-host-disease (GvHD)[J]. Blood, 2018, 132: 2207.
[3] Stein M N, Dumbrava E E, Teply B A, et al. PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: a phase 1 dose escalation trial[J]. Nature communications, 2024, 15(1): 10743.
[4] Wu Y, Chang T, Long Y, et al. Using gene editing to establish a safeguard system for pluripotent stem-cell-based therapies[J]. Iscience, 2019, 22: 409-422.
[5] Richard R E, Wood B, Zeng H, et al. Expansion of genetically modified primary human hemopoietic cells using chemical inducers of dimerization[J]. Blood, The Journal of the American Society of Hematology, 2000, 95(2): 430-436.
[6] Madadi Z, Akbari-Birgani S, Mohammadi S, et al. The effect of caspase-9 in the differentiation of SH-SY5Y cells[J]. European Journal of Pharmacology, 2021, 904: 174138.
[7] Romecín P A, Vinyoles M, López-Millán B, et al. Robust in vitro and in vivo immunosuppressive and anti-inflammatory properties of inducible caspase-9-mediated apoptotic mesenchymal stromal/stem cell[J]. Stem Cells Translational Medicine, 2022, 11(1): 88-96.
[8] Wu C, Hong S G, Winkler T, et al. Development of an inducible caspase-9 safety switch for pluripotent stem cell–based therapies[J]. Molecular therapy Methods & clinical development, 2014, 1.