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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 |
Both the hRS7-CL2A- and CL2-SN-38 conjugates significantly inhibited tumor growth compared to untreated (AUC14days P<0.002 vs. saline in COLO 205 model; AUC21days P<0.001 vs. saline in Capan-1 model), and a non-targeting anti-CD20 control ADC, hA20-CL2A-SN-38 (AUC14days P<0.003 in COLO-205 model; AUC35days: P<0.002 in Capan-1 model). At the end of the study (day 140) in the Capan-1 model, 50% of the mice treated with hRS7-CL2A-SN-38 and 40% of the hRS7-CL2-SN-38 mice were tumor-free, while only 20% of the hA20-ADC-treated animals had no visible sign of disease. Importantly, there were no differences in efficacy between the two specific conjugates in both the tumor models.[1]
Biodistribution of hRS7-CL2A-SN-38 The biodistributions of hRS7-CL2A-SN-38 or unconjugated hRS7 IgG were compared in mice bearing SK-MES-1 human squamous cell lung carcinoma xenografts (Suppl. Table S1), using the respective 111In-labeled substrates. A pharmacokinetic analysis was performed to determine the clearance of hRS7-CL2A-SN-38 relative to unconjugated hRS7 (Fig. 4A). The ADC cleared faster than the equivalent amount of unconjugated hRS7, with the ADC exhibiting ~40% shorter half-life and mean residence time. Nonetheless, this had a minimal impact on tumor uptake (Fig. 4B). While there were significant differences at the 24- and 48-h time-points, by 72 h (peak uptake) the amounts of both agents in the tumor were similar. Among the normal tissues, hepatic (Fig. 4C) and splenic (Fig 4D) differences were the most striking. At 24 h post-injection, there was >2-fold more hRS7-CL2A-SN-38 in the liver than hRS7 IgG. Conversely, in the spleen there was three-fold more parental hRS7 IgG present at peak uptake (48-h time-point) than hRS7-CL2A-SN-38. Uptake and clearance in the rest of the tissues generally reflected differences in the blood concentration.[1] |
| Toxicity/Toxicokinetics |
Tolerability of hRS7-CL2A-SN-38 in Swiss-Webster mice and Cynomolgus monkeys[1]
Swiss-Webster mice tolerated two doses over three days, each of 4, 8, and 12 mg SN-38/kg of the hRS7-CL2A-SN-38, with minimal transient weight loss (Suppl. Figure S2). No hematopoietic toxicity occurred and serum chemistries only revealed elevated aspartate transaminase (AST) and alanine transaminase (ALT) (Figure 5). Seven days after treatment, AST rose above normal levels (>298 U/L) in all three treatment groups (Fig. 5A), with the largest proportion of mice being in the 2 × 8 mg/kg group. However, by 15 days post-treatment, most animals were within the normal range. ALT levels were also above the normal range (>77 U/L) within seven days of treatment (Fig. 5B) and with evidence of normalization by Day 15. Livers from all these mice did not show histologic evidence of tissue damage (not shown). In terms of renal function, only glucose and chloride levels were somewhat elevated in the treated groups. At 2 × 8 mg/kg, 5 of 7 mice had slightly elevated glucose levels (range of 273 to 320 mg/dL, upper end of normal 263 mg/dL) that returned to normal by 15 days post-injection. Likewise, chloride levels were slightly elevated, ranging from 116 to 127 mmol/L (upper end of normal range 115 mmol/L) in the two highest dosage groups (57% in the 2 × 8 mg/kg group and 100% of the mice in the 2 × 12 mg/kg group), and remained elevated out to 15 days post-injection. This also could be indicative of gastrointestinal toxicity, since most chloride is obtained through absorption by the gut; however, at termination, there was no histologic evidence of tissue damage in any organ system examined (not shown). |
| References | |
| Additional Infomation |
Since Trop-2 is not expressed in mice, it was critically important to perform toxicity studies in monkeys that have a similar tissue expression of Trop-2 as humans. Monkeys tolerated 0.96 mg/kg/dose (~12 mg/m2) with mild and reversible toxicity, which extrapolates to a human dose of ~0.3 mg/kg/dose (~11 mg/m2). In a Phase I clinical trial of NK012, patients with solid tumors tolerated 28 mg/m2 of SN-38 every 3 weeks with Grade 4 neutropenia as dose-limiting toxicity (DLT). Likewise, Phase I clinical trials with ENZ-2208 revealed dose-limiting febrile neutropenia, with a recommendation to administer 10 mg/m2 every three weeks or 16 mg/m2 if patients were administered G-CSF. Since monkeys tolerated a cumulative human equivalent dose of 22 mg/m2, it is possible that even though hRS7 binds to a number of normal tissues, the MTD for a single treatment of the hRS7 ADC could be similar to that of the other non-targeting SN-38 agents. Indeed, the specificity of the anti-Trop-2 antibody did not appear to play a role in defining the DLT, since the toxicity profile was similar to that of irinotecan. More importantly, if anti-tumor activity can be achieved in humans as in mice that responded with human equivalent dose of just at 0.03 mg SN-38 equivalents/kg/dose, then significant anti-tumor responses could be realized clinically.
In conclusion, toxicology studies in monkeys, combined with in vivo human cancer xenograft models in mice have indicated that this ADC targeting Trop-2 is an effective therapeutic in several tumors of different epithelial origin, supporting future clinical testing.[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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