AP1903 (Rimiducid)

Rimiducid (AP1903) 会导致培养中的修饰细胞显着且呈剂量依赖性凋亡，EC50 约为 0.1 nM [1]。当存在 3 至 10 nM Rimiducid (AP1903) 时，可实现最大程度的杀灭作用，IC50 约为 0.2 nM。具有高水平 CD25 的 LV'VFas 转导的 T 细胞（上图）被去除，效率为 66%±7.5% (n=10)。 CD25 表达恢复至基线水平后，Rimiducid 治疗导致 63%±4.7% (n=9) 细胞死亡 [2]。

fumiducid（AP1903；静脉注射，0.01、0.1、1、10 和 100 mg/kg）以剂量依赖性方式降低血清人生长激素水平；半最大有效剂量为 0.4 ± 0.1 mg/kg [1]。

制备用 Fas 构建体逆转录病毒转导的克隆 HT1080 细胞系 (ATCC CCL-121)。通过 Alamar Blue 测定法测量与 Rimiducid（0.01 nM、0.1 nM、1 nM、10 nM、100 nM、1000 nM）过夜孵育后的细胞活力[1]。对于膜联蛋白 V 测定，将分选的 LV'VFas 转导的 T 细胞 (2×106 个细胞/mL) 与 10 nM Rimiducid 一起孵育。在指定时间，取出 2×105 个细胞的等分试样，用膜联蛋白 V-异硫氰酸荧光素染色，并通过流式细胞术进行分析[2]。

[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-permeable tacrolimus analogue and a protein dimerizer. It was designed to overcome limitations of current cellular immunotherapies used for cancer and other blood disorders by enhancing the control of the immune cell activity and function. When administered via chemically-inducible dimerization (CID) technologies, rimiducid binds to switch proteins and dimerizes them, triggering downstream signaling cascade. The combination use of rimiducid with immunotherapies for enhanced therapeutic effectiveness is currently under investigation.
Rimiducid is a lipid-permeable tacrolimus analogue with homodimerizing activity. Dimerizer drug AP1903 homodimerizes an analogue of human protein FKBP12 (Fv) which contains a single acid substitution (Phe36Val) so that AP1903 binds to wild-type FKBP12 with 1000-fold lower affinity. This agent is used to homodimerize the Fv-containing drug-binding domains of genetically engineered receptors such as the iCD40 receptor of the autologous dendritic cell vaccine BP-GMAX-CD1, resulting in receptor activation.

---

Drug Indication
Investigated for use/treatment in bone marrow transplant and graft versus host disease.
Treatment of graft versus host disease

---

Mechanism of Action
Rimiducid binds to a drug binding domain derived from human FK506-binding protein which is present on a modified form of inducible caspase-9. This binding results in dimerization and subsequent activation of caspase-9. This system was designed to function as a "safety switch" in CAR T-cell therapy used in hematological cancers. Retroviral vectors used in production of these modified cells preferentially integrate this gene nearby promoters associated with T-cell activation. This results in higher expression of the modified inducible caspase-9 product in activated T-cells. In practice, this allows for specific targeting of these active T-cells by rimiducid which results in a decrease in circulating cell numbers of over 90% in the setting of graft versus host disease. This specificity spares non-alloreactive T-cells and allows for successful reconstitution of the transplanted immune system from these cells.[24753538] Additionally, these non-alloreactive cells retain their sensitivity to rimiducid.

---

Pharmacodynamics
Rimiducis is used to activate inducible caspase-9 produced by a modified gene included in some CAR T-cell therapies. This activation produces rapid induction of apoptosis in activated modified T-cells and resolution of 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

262

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

注意： 该产品在溶液状态不稳定，请现配现用。

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (1.77 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

---

配方 2 中的溶解度: 2 mg/mL (1.42 mM) in 2% DMSO 98% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。