CL2A-SN-38

Camptothecins/DNA Topoisomerase I

将两种SN-38衍生物CL2-SN-38和CL2A-SN-38与抗Trop-2人源化抗体hRS7缀合。在体外对免疫偶联物的稳定性、结合性和细胞毒性进行了表征[1]。

在携带人结肠（COLO 205）或胰腺（Capan-1）肿瘤异种移植物的小鼠中，CL2A-SN-38联合抗Trop-2人源化抗体hRS7（腹膜内注射，0.2或0.4 mg/kg，每周两次， 4周）均能显着抑制肿瘤生长[1]。

CL2A-SN-38（M.W.1480）及其hRS7缀合物的制备以及稳定性、结合和细胞毒性研究如前所述进行，并在补充数据中介绍。制备细胞裂解物，并如补充数据中所述进行p21Waf1/Cip、p53和PARP（聚ADP核糖聚合酶）的免疫印迹。浓度、时间和一次抗体如图例所示[1]。

本研究中使用的所有人类癌症细胞系均购自美国典型培养物保藏中心。其中包括Calu-3（非小细胞肺癌）、SK-MES-1（鳞状细胞肺癌），COLO205（结肠腺癌），Capan-1和BxPC-3（胰腺腺癌）以及PC-3（前列腺腺癌）。人源化RS7 IgG和对照人源化抗-CD20（hA20 IgG，veltuzumab）和抗-CD22（hLL2 IgG，依帕珠单抗）抗体在Immunomedics，股份有限公司制备。伊立替康（20 mg/mL）从Hospira，股份有限公司获得[1]。

For all animal studies, the doses of SN-38 immunoconjugates and irinotecan are shown in SN-38 equivalents. Based on a mean SN-38/IgG substitution ratio of six, a dose of 500 μg ADC to a 20-gram mouse (25 mg/kg) contains 0.4 mg/kg of SN-38. Irinotecan doses are likewise shown as SN-38 equivalents (i.e., 40 mg irinotecan/kg is equivalent to 24 mg/kg of SN-38).
NCr female athymic nude (nu/nu) mice, 4–8 weeks old, and male Swiss-Webster mice, 10 weeks old, were purchased from Taconic Farms (Germantown, NY). All animal studies were approved by the Center for Molecular Medicine and Immunology’s Institutional Animal Care and Use Committee (IACUC). Tolerability studies were performed in Cynomolgus monkeys (Macaca fascicularis; 2.5–4 kg male and female) by SNBL USA, Ltd. after approval by SNBL USA’s IACUC.
Animals were implanted subcutaneously with different human cancer cell lines as described in the Supplemental Information. Tumor volume (TV) was determined by measurements in two dimensions using calipers, with volumes defined as: L x w2/2, where L is the longest dimension of the tumor and w the shortest. Tumors ranged in size between 0.10 to 0.47 cm3 when therapy began. Treatment regimens, dosages, and number of animals in each experiment are described in the Results. The lyophilized hRS7-CL2A-SN-38 and control ADC were reconstituted and diluted as required in sterile saline. All reagents were administered intraperitoneally (0.1 mL), except irinotecan, which was administered intravenously. The dosing regimen was influenced by our prior investigations, where the ADC was given every 4 days or twice weekly for varying lengths of time. This dosing frequency reflected a consideration of the conjugate’s serum half-life in vitro, in order to allow a more continuous exposure to the ADC.

[1]. Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res. 2011 May 15;17(10):3157-69.

C77H101CL4N11O26

1,738.506

1,479.68

C, 53.20; H, 5.86; Cl, 8.16; N, 8.86; O, 23.93

1279680-68-0

1279680-68-0

Light yellow to yellow solid powder

-0.1

409Ų

O=C(O[C@@]1(CC)C2=C(C(N3CC4=C(C5=CC(O)=CC=C5N=C4C3=C2)CC)=O)COC1=O)OCC6=CC=C(C=C6)NC([C@@H](NC(COCC(NCCOCCOCCOCCOCCOCCOCCOCCOCCN7N=NC(CNC(C8CCC(CC8)CN9C(C=CC9=O)=O)=O)=C7)=O)=O)CCCCN)=O.O=C(O)C(Cl)Cl.O=C(O)C(Cl)Cl

WWSNNYDLXHTRLZ-JGQYWRMXSA-N

InChI=1S/C73H97N11O22.2C2H2Cl2O2/c1-3-55-56-39-54(85)16-17-60(56)79-67-57(55)44-83-62(67)40-59-58(70(83)92)46-104-71(93)73(59,4-2)106-72(94)105-45-50-10-14-52(15-11-50)77-69(91)61(7-5-6-20-74)78-64(87)48-103-47-63(86)75-21-23-95-25-27-97-29-31-99-33-35-101-37-38-102-36-34-100-32-30-98-28-26-96-24-22-82-43-53(80-81-82)41-76-68(90)51-12-8-49(9-13-51)42-84-65(88)18-19-66(84)89;2*3-1(4)2(5)6/h10-11,14-19,39-40,43,49,51,61,85H,3-9,12-13,20-38,41-42,44-48,74H2,1-2H3,(H,75,86)(H,76,90)(H,77,91)(H,78,87);2*1H,(H,5,6)/t49?,51?,61-,73-;;/m0../s1

4-((S)-2-(4-aminobutyl)-35-(4-((4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexane-1-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonaoxa-3,9-diazapentatriacontanamido)benzyl ((S)-4,11-diethyl-9-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl) carbonate bis(2,2-dichloroacetate)

CL2A-SN-38; CL2A-SN 38; CL2A-SN38; CL2ASN-38; CL2A SN 38; CL2ASN38; CL2A-SN38 DCA salt; CL2A-SN38 dichloroacetic acid.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), away from moisture and light.

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 (~67.54 mM）

Solubility in Formulation 1: 2.08 mg/mL (1.40 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (1.40 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (1.40 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+ 40% PEG300+ 5% Tween-80+ 45% saline: 2.08 mg/mL (1.40 mM)

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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。