Antibody Conjugates of 7-Ethyl-10-hydroxycamptothecin (SN-38) for Targeted Cancer Chemotherapy

Moon, Sung-Ju; Govindan, Serengulam V.; Cardillo, Thomas M.; D'Souza, Christopher; Hansen, Hans J.; Goldenberg, David M.

doi:10.1021/jm800719t

Cited by 129 publications

(122 citation statements)

References 26 publications

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“…Although the more recently approved ultratoxic ADCs use linkers that bind the drug stably while in serum, as premature release of those agents would increase toxicity and reduce their therapeutic window, our in vivo experience revealed the optimal therapeutic activity for an SN-38 ADC required a linker that neither held the drug stably nor released it too early (9,10,21). This conjugate system also permits the site-specific coupling of nearly 8 molecules of SN-38 per IgG without affecting the physiochemical nature, immunoreactivity, or the pharmacokinetics of the conjugate compared with unconjugated IgG (12).…”

Section: Discussionmentioning

confidence: 96%

“…Selecting the best conjugate relied on efficacy studies in human tumor xenograft/mouse models, with the linker designation CL2 providing the best responses (9,10). Interestingly, in vitro serum stability studies of the initial 3 candidate conjugates revealed that SN-38 was released at different rates, with one having a half-life of about 10 hours, whereas another was highly stable; yet, the selected CL2-linked conjugate had an intermediate stability in serum of 36 hours.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)

Sharkey

McBride

Cardillo

et al. 2015

Clinical Cancer Research

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137

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Purpose: This study examined the delivery of SN-38 to Trop-2-expressing tumors and assessed the constitutive products in the serum, liver, and small intestine in nude mice bearing human tumor xenografts (Capan-1 or NCI-N87) given a single injection of irinotecan (40 mg/kg; $0.8 mg/mouse, containing $460 mg SN-38 equivalents) or sacituzumab govitecan (IMMU-132), an antibody-drug conjugate composed of a humanized anti-Trop-2 IgG coupled site specifically with an average of 7.6 molecules of SN-38.Experimental Design: At select times, tissues were extracted and concentrations of the products measured by reversed-phase high-performance liquid chromatography (HPLC).Results: In serum, >98% irinotecan cleared within 5 minutes; peak levels of SN-38 and SN-38G (glucuronidated SN-38) were detected in equal amounts at this time, and no longer detected after 6 to 8 hours. IMMU-132 was detected in the serum over 3 days, and at each interval, !95% of total SN-38 was bound to the antibody. Intact IMMU-132 cleared with a half-life of 14 hours, which closely reflected the in vitro rate of SN-38 released from the conjugate in mouse serum (i.e., 17.5 hours), whereas the IgG portion of the conjugate cleared with a half-life of 67.1 hours. In vitro and in vivo studies disclosed IgG-bound SN-38 was protected from glucuronidation. Area under the curve (AUC) analysis indicated that IMMU-132 delivers 20-fold to as much as 136-fold more SN-38 to tumors than irinotecan, with tumor:blood ratios favoring IMMU-132 by 20-to 40-fold. Intestinal concentrations of SN-38/SN-38G also were 9-fold lower with IMMU-132.Conclusions: These studies confirm a superior SN-38 tumor delivery by IMMU-132 compared with irinotecan. Clin Cancer Res; 21(22); 5131-8. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)

Sharkey

McBride

Cardillo

et al. 2015

Clinical Cancer Research

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137

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“…Assays used to compare cell binding of the unconjugated and conjugated milatuzumab with antigen-positive cells, and cytotoxicity testing using the MTS dye reduction method (Promega), have been reported previously (27).…”

Section: In Vitro Cell Binding and Cytotoxicitymentioning

confidence: 99%

“…Because a milatuzumab-doxorubicin conjugate was highly active in models of hematologic tumors (13,14), it was a logical choice for this assessment. However, we developed procedures for coupling the highly potent topoisomerase I inhibitor, SN-38, to antibodies (26,27). SN-38 is the active form of irinotecan, whose pharmacology and metabolism are well known (28,29).…”

Section: Introductionmentioning

confidence: 99%

Milatuzumab–SN-38 Conjugates for the Treatment of CD74+ Cancers

Govindan

Cardillo

Sharkey

et al. 2013

Molecular Cancer Therapeutics

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CD74 is an attractive target for antibody-drug conjugates (ADC), because it internalizes and recycles after antibody binding. CD74 mostly is associated with hematologic tumors but is expressed also in solid cancers. Therefore, ADCs of the humanized anti-CD74 antibody, milatuzumab, were examined for the therapy of CD74-expressing solid tumors. Milatuzumab-doxorubicin and two milatuzumab-SN-38 conjugates with cleavable linkers, differing in their stability in serum and how they release SN-38 in the lysosome, were prepared. CD74 expression was determined by flow cytometry and immunohistology. In vitro cytotoxicity and in vivo therapeutic studies were conducted in the human cancer cell lines A-375 (melanoma), HuH-7 and Hep-G2 (hepatoma), Capan-1 (pancreatic), NCI-N87 (gastric), and Raji Burkitt lymphoma. The milatuzumab-SN-38 ADC was compared with SN-38 ADCs prepared with anti-Trop-2 and anti-CEACAM6 antibodies in xenografts expressing their target antigens. Milatuzumab-doxorubicin was most effective in the lymphoma model, whereas in A-375 and Capan-1 solid tumors, only milatuzumab-SN-38 showed a therapeutic benefit. Despite much lower surface expression of CD74 than Trop-2 or CEACAM6, milatuzumab-SN-38 had similar efficacy in Capan-1 as anti-Trop-2-SN-38, but in NCI-N87, anti-CEACAM6 and anti-Trop-2 conjugates were superior. Studies in two hepatoma lines at a single dose level showed significant benefit over saline controls but not against an irrelevant immunoglobulin G conjugate. CD74 is a suitable target for ADCs in some solid tumor xenografts, with efficacy largely influenced by uniformity of CD74 expression and with SN-38 conjugates providing the best therapeutic responses; SN-38 conjugates were preferable in solid cancers, whereas doxorubicin ADC was better in lymphoma tested. Mol Cancer Ther; 12(6); 968-78. Ó2013 AACR.

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“…These derivatives of SN38 were synthesized according to the reported references with modifications. [33][34][35] SN38 (1 g, 2.55 mmol) and DIBOC (0.61 g, 2.81 mmol) were stirred in anhydrous dichloromethane (DCM) with a catalytic amount of anhydrous pyridine for 14 hours at room temperature. The reaction mixture was then washed several times with 0.5% NaHCO 3 and 0.1 mol/L HCl.…”

Section: Animals and Cell Linementioning

confidence: 99%

Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

Liu¹,

Piao²,

Gao³

et al. 2015

IJN

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7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C 10 -OH)SN38 and chitosan-(C 20 -OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C 10 -OH)SN38 (CS-(10s)SN38) and chitosan-(C 20 -OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC) 0–24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P <0.01). A larger AUC 0–24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 ( P <0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg ( P <0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C 20 -OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.

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Antibody Conjugates of 7-Ethyl-10-hydroxycamptothecin (SN-38) for Targeted Cancer Chemotherapy

Cited by 129 publications

References 26 publications

Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)

Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)

Milatuzumab–SN-38 Conjugates for the Treatment of CD74+ Cancers

Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

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