Rimiducid (AP1903) causes significant and dose-dependent apoptosis of modified cells in culture, with an EC50 of around 0.1 nM [1]. Maximum killing occurs in the presence of 3 to 10 nM Rimiducid (AP1903), with an IC50 of around 0.2 nM. LV'VFas-transduced T cells (upper panel) with high levels of CD25 were removed with an efficiency of 66%±7.5% (n=10). After CD25 expression recovered to baseline levels, Rimiducid therapy resulted in 63%±4.7% (n=9) cell death [2].

Serum human growth hormone levels are reduced in a dosage-dependent manner by fumiducid (AP1903; iv, 0.01, 0.1, 1, 10, and 100 mg/kg); the half-maximum efficacious dose is 0.4 ± 0.1 mg/kg [1].

[1]. Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42.

[2]. A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood. 2001 Mar 1;97(5):1249-57.

Rimiducid is a lipid-soluble tacrolimus analog and a protein dimerizing agent. It is designed to overcome the limitations of current cell immunotherapies used to treat cancer and other blood disorders by enhancing control over the activity and function of immune cells. When administered via chemically induced dimerization (CID) technology, Rimiducid binds to and dimers a switch protein, triggering a downstream signaling cascade. The combination of Rimiducid with immunotherapy is currently being investigated to enhance therapeutic efficacy. Rimiducid is a lipid-soluble tacrolimus analog with homodimerizing activity. The dimerizing agent AP1903 can homodimerize an analog of the human protein FKBP12 (Fv) containing a one-amino acid substitution (Phe36Val), thus reducing the binding affinity of AP1903 to wild-type FKBP12 by 1000-fold. This drug is used to homodimerize the drug-binding domain containing the Fv fragment of genetically engineered receptors (such as the iCD40 receptor of the autologous dendritic cell vaccine BP-GMAX-CD1), thereby activating the receptor.

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Drug Indications
It has been investigated for the treatment of bone marrow transplantation and graft-versus-host disease.
Treatment of Graft-versus-Host Disease
Mechanism of Action
Rimiducid binds to a drug-binding domain derived from the human FK506 binding protein, which is located on a modified inducible caspase-9. This binding leads to caspase-9 dimerization and subsequent activation. This system is designed as a “safety switch” in CAR-T cell therapy for hematologic malignancies. The retroviral vector used to produce these modified cells preferentially integrates this gene near a promoter associated with T cell activation. This results in increased expression levels of the modified inducible caspase-9 product in activated T cells. In effect, this allows rimiducid to specifically target these activated T cells, thereby reducing the number of circulating cells by more than 90% in cases of graft-versus-host disease. This specificity does not affect allogeneic reactive T cells and allows for the successful reconstruction of the transplanted immune system using these cells. [24753538] Furthermore, these allogeneic reactive cells remain sensitive to rimiducid.

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Pharmacodynamics
Rimiducid is used to activate inducible caspase-9 produced by a modified gene contained in certain CAR-T cell therapies. This activation rapidly induces apoptosis in activated modified T cells and alleviates the signs and symptoms of graft-versus-host disease within 24 hours.

C78H98N4O20

1411.63

1410.677

195514-63-7

16135625

White to light yellow solid powder

1.2±0.1 g/cm3

1307.5±65.0 °C at 760 mmHg

744.5±34.3 °C

0.0±0.3 mmHg at 25°C

1.566

10.39

2

20

39

102

2330

6

CC[C@@H](C1=CC(=C(C(=C1)OC)OC)OC)C(=O)N2CCCC[C@H]2C(=O)O[C@H](CCC3=CC(=C(C=C3)OC)OC)C4=CC(=CC=C4)OCC(=O)NCCNC(=O)COC5=CC=CC(=C5)[C@@H](CCC6=CC(=C(C=C6)OC)OC)OC(=O)[C@@H]7CCCCN7C(=O)[C@@H](CC)C8=CC(=C(C(=C8)OC)OC)OC

GQLCLPLEEOUJQC-WFMNNBDOSA-N

InChI=1S/C78H98N4O20/c1-13-57(53-43-67(93-7)73(97-11)68(44-53)94-8)75(85)81-37-17-15-25-59(81)77(87)101-61(31-27-49-29-33-63(89-3)65(39-49)91-5)51-21-19-23-55(41-51)99-47-71(83)79-35-36-80-72(84)48-100-56-24-20-22-52(42-56)62(32-28-50-30-34-64(90-4)66(40-50)92-6)102-78(88)60-26-16-18-38-82(60)76(86)58(14-2)54-45-69(95-9)74(98-12)70(46-54)96-10/h19-24,29-30,33-34,39-46,57-62H,13-18,25-28,31-32,35-38,47-48H2,1-12H3,(H,79,83)(H,80,84)/t57-,58-,59+,60+,61+,62+/m0/s1

(S,2R,2'R)-(1R,1'R)-((((ethane-1,2-diylbis(azanediyl))bis(2-oxoethane-2,1-diyl))bis(oxy))bis(3,1-phenylene))bis(3-(3,4-dimethoxyphenyl)propane-1,1-diyl) bis(1-((S)-2-(3,4,5-trimethoxyphenyl)butanoyl)piperidine-2-carboxylate)

AP-1903 Rimiducid AP 1903 AP1903

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~70.84 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (1.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 2: 2 mg/mL (1.42 mM) in 2% DMSO 98% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)