CL2 Linker - CAS 2270986-66-6

CL2 Linker - CAS 2270986-66-6 Catalog number: BADC-00673

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Category
ADCs Linker
Product Name
CL2 Linker
CAS
2270986-66-6
Catalog Number
BADC-00673
Molecular Formula
C68H103N11O22
Molecular Weight
1426.61
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Canonical SMILES
OCC(COC(N(C)CCN(C)C(OCC(C=C1)=CC=C1NC([C@H](CCCCNC(OC(C)(C)C)=O)NC([C@@H](NC(CCOCCOCCOCCOCCOCCOCCOCCOCCN2C=C(CNC(CCCCCN3C(C=CC3=O)=O)=O)N=N2)=O)CC4=CC=CC=C4)=O)=O)=O)=O)=O
InChI
InChI=1S/C68H103N11O22/c1-68(2,3)101-65(88)69-25-12-11-16-57(63(86)71-54-20-18-53(19-21-54)50-99-66(89)76(4)27-28-77(5)67(90)100-51-56(81)49-80)73-64(87)58(46-52-14-8-6-9-15-52)72-60(83)24-30-91-32-34-93-36-38-95-40-42-97-44-45-98-43-41-96-39-37-94-35-33-92-31-29-78-48-55(74-75-78)47-70-59(82)17-10-7-13-26-79-61(84)22-23-62(79)85/h6,8-9,14-15,18-23,48,57-58,80H,7,10-13,16-17,24-47,49-51H2,1-5H3,(H,69,88)(H,70,82)(H,71,86)(H,72,83)(H,73,87)/t57-,58-/m0/s1
InChIKey
BGFZCTPREVDQQQ-YQOHNZFASA-N
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1.Antibody conjugates of 7-ethyl-10-hydroxycamptothecin (SN-38) for targeted cancer chemotherapy
Moon SJ, Govindan SV, Cardillo TM, D'Souza CA, Hansen HJ, Goldenberg DM
CPT-11 is a clinically used cancer drug, and it is a prodrug of the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin). To bypass the need for the in vivo conversion of CPT-11 and increase the therapeutic index, bifunctional derivatives of SN-38 were prepared for use in antibody-based targeted therapy of cancer. The general synthetic scheme incorporated an acetylene-azide click cycloaddition step in the design, a short polyethylene glycol spacer for aqueous solubility, and a maleimide group for conjugation. Conjugates of a humanized anti-CEACAM5 monoclonal antibody, hMN-14, prepared using these SN-38 derivatives were evaluated in vitro for stability in buffer and human serum and for antigen-binding and cytotoxicity in a human colon adenocarcinoma cell line. Conjugates of hMN-14 and SN-38 derivatives 16 and 17 were found promising for further development.
2.Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys
Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM
PURPOSE: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.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. 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.RESULTS: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. 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.
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