Antibody–drug conjugates—A new wave of cancer drugs

Bouchard, Hervé; Viskov, Christian; García‐Echeverría, Carlos

doi:10.1016/j.bmcl.2014.10.021

Cited by 167 publications

(138 citation statements)

References 29 publications

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“…The selectivity relies on this differential expression being sufficient to allow a killing action on the target cells without substantial damage to normal tissues. Our discriminating Fab thus might be a potential candidate for conversion of its single chain to clinically relevant-molecules: 1) conjugated with chemotherapy drug, 51 2) linked with an immunotoxin, 52 or 3) formatted as an IgG with effector functions such as antibody-dependent cell-mediated cytotoxicity. 53 In addition, studies on genetically modified T cells with CARs, including anti-mesothelin CAR T cells, report significant efficacy in different malignancies.…”

Section: Discussionmentioning

confidence: 99%

A new anti-mesothelin antibody targets selectively the membrane-associated form

Asgarov

Balland

Tirole

et al. 2017

mAbs

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Mesothelin is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that shows promise as a target for antibody-directed cancer therapy. High levels of soluble forms of the antigen represent a barrier to directing therapy to cellular targets. The ability to develop antibodies that can selectively discriminate between membrane-bound and soluble conformations of a specific protein, and thus target only the membrane-associated antigen, is a substantive issue. We show that use of a tolerance protocol provides a route to such discrimination. Mice were tolerized with soluble mesothelin and a second round of immunizations was performed using mesothelin transfected P815 cells. RNA extracted from splenocytes was used in phage display to obtain mesothelin-specific antigen-binding fragments (Fabs) that were subsequently screened by flow cytometry and ELISA. This approach generated 147 different Fabs in 34 VH-CDR3 families. Utilizing competition assays with soluble protein and mesothelin-containing serum obtained from metastatic cancer patients, 10 of these 34 VH-CDR3 families were found to bind exclusively to the membrane-associated form of mesothelin. Epitope mapping performed for the 1H7 clone showed that it does not recognize GPI anchor. VH-CDR3 sequence analysis of all Fabs showed significant differences between Fabs selective for the membrane-associated form of the antigen and those that recognize both membrane bound and soluble forms. This work demonstrates the potential to generate an antibody specific to the membrane-bound form of mesothelin. 1H7 offers potential for therapeutic application against mesothelin-bearing tumors, which would be largely unaffected by the presence of the soluble antigen.

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Section: Discussionmentioning

confidence: 99%

A new anti-mesothelin antibody targets selectively the membrane-associated form

Asgarov

Balland

Tirole

et al. 2017

mAbs

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“…However, this technology has faced many challenges, but with 3 conjugates gaining FDA approval, each using drugs that are active at picomolar concentrations (so-called ultratoxic drugs), it appeared that the major hurdles facing this technology had been overcome and that a core platform on which similar agents could be developed was available (1)(2)(3)(4)(5). Our group departed from the current popular approach, and instead developed an ADC with a more moderately toxic agent, SN-38.…”

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

124

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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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“…Its natural analogues from L. majuscula, curacin A, B, C and D (Gerwick et al 1994;Yoo and Gerwick 1995;Márquez et al 1998) were unable to produce anticancer effectivity during in vivo animal trails; but, synthetic analogue(s) of curacin served the development of anticancer agents (Wipf et al 2004). Updated clinical information reveals that most Lyngbya-compounds, their several synthetic analogues individually and antibody-drug conjugates (ADCs) are in the process of development as anticancer drugs (Bouchard et al 2014; Table 2). ADCs are nearer to development as potent anticancer drugs, since those have proved as the sought after anticancer agents, simulating the classical magic bullet theory of Paul Ehrlich in the use of an antibiotic.…”

Section: Cyanobacterial Bioactive Molecules Under Clinical Trialsmentioning

confidence: 98%

Anticancer compounds from cyanobacterium Lyngbya species: a review

Swain

Padhy

Singh

2015

Antonie van Leeuwenhoek

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The use of synthetic anticancer drugs and other methods followed in cancer therapy have several side effects; and ineffective methods or drugs give a way to the emergence of drug resistant cancer cells, with the intrinsic metastasis as the aftermath. Anticancer efficacy of many cyanobacterial compounds has been claimed in literature. This review considers 144 compounds isolated and characterized from seven species of the non-nitrogen fixing filamentous cyanobacterium Lyngbya, as the source of antineoplastic agents, which have been screened primarily with cancer cell lines. Structure and information of Lyngbya compounds were retrieved from databases, PubChem, ChemSpider and ChEBI. Information and clinical status of Lyngbya compounds are summarized, and those might be the future anticancer drugs for drug-resistant cancer cells even, as complementary/adduct drugs, if pursued thoroughly in pharmacology and pharmaceutics.

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Antibody–drug conjugates—A new wave of cancer drugs

Cited by 167 publications

References 29 publications

A new anti-mesothelin antibody targets selectively the membrane-associated form

A new anti-mesothelin antibody targets selectively the membrane-associated form

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

Anticancer compounds from cyanobacterium Lyngbya species: a review

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