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CL2-SN-38 is a cleavable linker-drug conjugate used for the synthesis of antibody drug conjugates (ADC). As a part of the antibody drug conjugate (ADC), it can conjugate with the anti-Trop-2-humanized antibody hRS7. The anti-Trop-2 hRS7-CL2A-SN-38 ADC exhibits potent and highly specific anticancer effects against a range of human solid tumor types.
| Targets |
ADC drug-linker conjugate; Camptothecins/DNA Topoisomerase I
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| ln Vitro |
The hRS7 conjugates of the two SN-38 derivatives were equivalent in drug substitution (∼ 6), cell binding (K(d) ∼ 1.2 nmol/L), cytotoxicity (IC(50) ∼ 2.2 nmol/L), and serum stability in vitro (t/(½) ∼ 20 hours). Exposure of cells to the ADC demonstrated signaling pathways leading to PARP cleavage, but differences versus free SN-38 in p53 and p21 upregulation were noted[1].
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| ln Vivo |
Significant antitumor effects were produced by hRS7-SN-38 at nontoxic doses in mice bearing Calu-3 (P ≤ 0.05), Capan-1 (P < 0.018), BxPC-3 (P < 0.005), and COLO 205 tumors (P < 0.033) when compared to nontargeting control ADCs. Mice tolerated a dose of 2 × 12 mg/kg (SN-38 equivalents) with only short-lived elevations in ALT and AST liver enzyme levels. Cynomolgus monkeys infused with 2 × 0.96 mg/kg exhibited only transient decreases in blood counts, although, importantly, the values did not fall below normal ranges.
Conclusions: The anti-Trop-2 hRS7-CL2A-SN-38 ADC provides significant and specific antitumor effects against a range of human solid tumor types. It is well tolerated in monkeys, with tissue Trop-2 expression similar to humans, at clinically relevant doses, and warrants clinical investigation[1].
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| Cell Assay |
Experimental design: Two SN-38 derivatives, CL2-SN-38 and CL2A-SN-38, were conjugated to the anti-Trop-2-humanized antibody, hRS7. The immunoconjugates were characterized in vitro for stability, binding, and cytotoxicity[1].
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| Animal Protocol |
Evaluate the efficacy of an SN-38-anti-Trop-2 antibody-drug conjugate (ADC) against several human solid tumor types, and to assess its tolerability in mice and monkeys, the latter with tissue cross-reactivity to hRS7 similar to humans.
Efficacy was tested in five different human solid tumor-xenograft models that expressed Trop-2 antigen. Toxicity was assessed in mice and in Cynomolgus monkeys[1]. |
| ADME/Pharmacokinetics |
Compared with the untreated group, both hRS7-CL2A- and CL2-SN-38 conjugates significantly inhibited tumor growth (AUC 14 days in the COLO 205 model, P < 0.002 vs. saline group; AUC 21 days in the Capan-1 model, P < 0.001 vs. saline group), and also showed significant inhibitory effects compared with the non-targeted anti-CD20 control antibody conjugate hA20-CL2A-SN-38 (AUC 14 days in the COLO-205 model, P < 0.003; AUC 35 days in the Capan-1 model, P < 0.002). In the Capan-1 model, at the end of the study (day 140), 50% and 40% of mice in the hRS7-CL2A-SN-38 treatment group and the hRS7-CL2-SN-38 treatment group, respectively, showed complete tumor regression, while only 20% of mice in the hA20-ADC treatment group showed no obvious signs of disease. Importantly, there was no difference in efficacy between the two specific conjugates in either tumor model. [1] Biodistribution of hRS7-CL2A-SN-38 was compared in mice carrying SK-MES-1 human squamous cell lung cancer xenografts using the corresponding 111In labeled substrates (Supplementary Table S1). Pharmacokinetic analysis was performed to determine the clearance of hRS7-CL2A-SN-38 relative to unconjugated hRS7 (Figure 4A). The ADC was cleared faster than an equivalent amount of unconjugated hRS7, and the half-life and mean residence time of the ADC were reduced by approximately 40%. Nevertheless, this had little effect on tumor uptake (Figure 4B). Although there were significant differences at 24 and 48 hours post-injection, the levels of the two drugs in the tumor were similar by 72 hours (peak up). The differences were most pronounced in the liver (Fig. 4C) and spleen (Fig. 4D) in normal tissues. At 24 hours post-injection, the levels of hRS7-CL2A-SN-38 in the liver were more than twice those of hRS7 IgG. In contrast, in the spleen, at the peak absorption point (48-hour time), the levels of parental hRS7 IgG were three times those of hRS7-CL2A-SN-38. Absorption and clearance in other tissues generally reflected differences in blood concentration. [1]
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| Toxicity/Toxicokinetics |
Tolerance to hRS7-CL2A-SN-38 in Swiss-Webster mice and cynomolgus monkeys [1]
Swiss-Webster mice tolerated two doses of hRS7-CL2A-SN-38 over three days at doses of 4, 8, and 12 mg/kg, with only a slight, transient decrease in body weight (Supplementary Figure S2). No hematopoietic toxicity occurred, and serum biochemistry showed only elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (Figure 5). After 7 days of treatment, AST levels in all three treatment groups were elevated above normal (>298 U/L) (Figure 5A), with the highest proportion of mice in the 2 × 8 mg/kg group. However, by day 15 after treatment, AST levels in most animals returned to normal. ALT levels were also elevated above normal (>77 U/L) during the first 7 days of treatment (Figure 5B) and returned to normal by day 15. No histological evidence of tissue damage was shown in the livers of any of these mice (not shown). Regarding renal function, only the treatment groups showed slight increases in glucose and chloride levels. In the 2 × 8 mg/kg dose group, 5 out of 7 mice showed mild elevations in glucose levels (range 273 to 320 mg/dL, upper limit of normal 263 mg/dL), which returned to normal 15 days post-injection. Similarly, in the two highest dose groups, chloride levels were also slightly elevated, ranging from 116 to 127 mmol/L (upper limit of normal 115 mmol/L) (57% in the 2 × 8 mg/kg group and 100% in the 2 × 12 mg/kg group), and remained elevated for 15 days post-injection. This could also be an indication of gastrointestinal toxicity, as most chloride is absorbed through the intestines; however, no histological evidence of tissue damage was found in any organ system examined at the end of the experiment (not shown). |
| References | |
| Additional Infomation |
Since mice do not express Trop-2, toxicity studies in monkeys, where Trop-2 tissue expression is similar to that in humans, are crucial. Monkeys tolerated a dose of 0.96 mg/kg/dose (approximately 12 mg/m²) well, experiencing only mild and reversible toxicities, which extrapolates to a human dose of approximately 0.3 mg/kg/dose (approximately 11 mg/m²). In the Phase I clinical trial of NK012, patients with solid tumors tolerated SN-38 at 28 mg/m² every 3 weeks, with a dose-limiting toxicity (DLT) of grade 4 neutropenia. Similarly, the Phase I clinical trial of ENZ-2208 also showed a dose-limiting toxicity of febrile neutropenia, recommending a dose of 10 mg/m² every 3 weeks, increasing to 16 mg/m² if the patient is concurrently receiving G-CSF treatment. Since monkeys can tolerate a cumulative human equivalent dose of 22 mg/m², the maximum tolerated dose (MTD) of a single treatment with an hRS7 antibody-drug conjugate (ADC) may be similar to that of other non-targeting SN-38 drugs, even though hRS7 binds to a variety of normal tissues. In fact, the specificity of the anti-Trop-2 antibody does not appear to affect the determination of dose-limiting toxicity (DLT), as its toxicity profile is similar to that of irinotecan. More importantly, if the drug can produce antitumor activity in humans at only 0.03 mg SN-38 equivalent/kg/dose, as it has in mice, then significant antitumor efficacy may be achieved clinically. In summary, the toxicology studies in monkeys combined with a human xenograft model in mice suggest that this Trop-2-targeting ADC has therapeutic effects on tumors of various epithelial origins, supporting future clinical trials. [1]
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| Molecular Formula |
C82H106N12O23
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|---|---|
| Molecular Weight |
1627.78566217422
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| Exact Mass |
1626.75
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| Elemental Analysis |
C, 54.78; H, 5.88; Cl, 7.52; N, 8.91; O, 22.91
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| CAS # |
1036969-20-6
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| Related CAS # |
1036969-20-6;
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| PubChem CID |
25139037
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| Appearance |
Light yellow to green yellow solid powder
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| LogP |
1.2
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| Hydrogen Bond Donor Count |
7
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| Hydrogen Bond Acceptor Count |
27
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| Rotatable Bond Count |
54
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| Heavy Atom Count |
117
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| Complexity |
3280
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O=C(C1CCC(CN2C(C=CC2=O)=O)CC1)NCC1=CN(CCOCCOCCOCCOCCOCCOCCOCCOCCNC(COCC(N[C@@H](CC2C=CC=CC=2)C(N[C@H](C(NC2C=CC(=CC=2)COC(=O)O[C@@]2(C(=O)OCC3C(N4CC5=C(CC)C6C=C(C=CC=6N=C5C4=CC2=3)O)=O)CC)=O)CCCCN)=O)=O)=O)N=N1
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| InChi Key |
SSDFVXUQLUAHIC-DPMVZHECSA-N
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| InChi Code |
InChI=1S/C82H106N12O23/c1-3-62-63-45-61(95)21-22-67(63)88-75-64(62)50-93-70(75)46-66-65(79(93)103)52-115-80(104)82(66,4-2)117-81(105)116-51-57-15-19-59(20-16-57)86-77(101)68(12-8-9-25-83)89-78(102)69(44-55-10-6-5-7-11-55)87-72(97)54-114-53-71(96)84-26-28-106-30-32-108-34-36-110-38-40-112-42-43-113-41-39-111-37-35-109-33-31-107-29-27-92-49-60(90-91-92)47-85-76(100)58-17-13-56(14-18-58)48-94-73(98)23-24-74(94)99/h5-7,10-11,15-16,19-24,45-46,49,56,58,68-69,95H,3-4,8-9,12-14,17-18,25-44,47-48,50-54,83H2,1-2H3,(H,84,96)(H,85,100)(H,86,101)(H,87,97)(H,89,102)/t56?,58?,68-,69-,82-/m0/s1
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| Chemical Name |
[4-[[(2S)-6-amino-2-[[(2S)-2-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-[[[4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarbonyl]amino]methyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethoxy]acetyl]amino]-3-phenylpropanoyl]amino]hexanoyl]amino]phenyl]methyl [(19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-19-yl] carbonate
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| Synonyms |
CL2-SN-38; CL2-SN 38; CL2-SN38; N-[32-[4-[[[[4-[(2,5-Dihydro-2,5-dioxo-1H-pyrrol-1-yl)methyl]cyclohexyl]carbonyl]amino]methyl]-1H-1,2,3-triazol-1-yl]-1,5-dioxo-3,9,12,15,18,21,24,27,30-nonaoxa-6-azadotriacont-1-yl]-L-phenylalanyl-N-[4-[[[[[(4S)-4,11-diethyl-3,4,12,14-tetrahydro-9-hydrox; Cl2-SN-38 (dichloroacetic acid salt); SCHEMBL16062728; CL2-SN-38 DCA; CL2-SN-38 2,2-dichloro-acetic acid salt
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| HS Tariff Code |
2934.99.9001
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| Storage |
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, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~61.43 mM）
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (1.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (1.54 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 25.0 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. View More
Solubility in Formulation 3: ≥ 2.2 mg/mL (1.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10% DMSO+ 40% PEG300+ 5% Tween-80+ 45% saline: ≥ 2.5 mg/mL (1.54 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.6143 mL | 3.0716 mL | 6.1433 mL | |
| 5 mM | 0.1229 mL | 0.6143 mL | 1.2287 mL | |
| 10 mM | 0.0614 mL | 0.3072 mL | 0.6143 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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