A Traceless Vascular‐Targeting Antibody–Drug Conjugate for Cancer Therapy

Bernardes, Gonçalo J. L.; Casi, Giulio; Trüssel, Sabrina; Hartmann, Isabelle; Schwager, Kathrin; Scheuermann, Jörg; Neri, Dario

doi:10.1002/ange.201106527

Cited by 31 publications

(19 citation statements)

References 30 publications

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“…and 6 hours [ Figure 3B]. These results are in keeping with the ones previously reported by our group with similar fluorescently-labeled derivatives [17,18,30], indicating that the acetazolamide moiety can deliver different types of payloads to SKRC-52-positive tumors.…”

Section: Synthesis and Tumor-targeting Properties Of Acetazolamide Desupporting

confidence: 90%

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Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Cazzamalli

Corso

Neri

2016

Molecular Cancer Therapeutics

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In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, causing unwanted toxicities and preventing dose escalation to therapeutically active regimens. Here, we show that acetazolamide derivatives, which bind to carbonic anhydrase IX (CAIX) on the surface of kidney cancer cells, selectively deliver payloads at the site of disease, sparing normal organs. Biodistribution studies, performed in tumor-bearing mice with acetazolamide derivatives bearing a technetium-99m chelator complex or a red fluorophore as payload, revealed a preferential tumor accumulation of the compound at doses up to 560 nmol/Kg. The percentage of injected dose per gram in the tumor was dose-dependent and revealed optimal tumor:organ ratios at 140 nmol/Kg, with a tumor:blood ratio of 80:1 at 6 h. Acetazolamide, coupled to potent cytotoxic drugs via a dipeptide linker, exhibited a potent antitumor activity in nude mice bearing SKRC-52 renal cell carcinomas, while drug derivatives devoid of the acetazolamide moiety did not exhibit any detectable anticancer activity at the same doses. The observation of tumor regression with a noninternalizing ligand and with different cytotoxic moieties (MMAE and PNU-159682) indicates a general mechanism of action, based on the selective accumulation of the product on tumor cells, followed by the extracellular proteolytic release of the cytotoxic payload at the neoplastic site and the subsequent drug internalization into tumor cells. Acetazolamide-based drug conjugates may represent a promising class of targeted agents for the treatment of metastatic kidney cancer, as the majority of human clear cell renal cell carcinomas are strongly positive for CAIX.

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Section: Synthesis and Tumor-targeting Properties Of Acetazolamide Desupporting

confidence: 90%

“…This concept, however, has recently been challenged, as potent and selective anticancer activity has been observed with ADCs and SMDCs specific to antigens, which do not internalize [19,20,[28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Cazzamalli

Corso

Neri

2016

Molecular Cancer Therapeutics

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“…Cell culture: cell lines, incubation, and manipulation conditions Transfected CHO-S cells (Invitrogen) were cultured in suspension in PowerCHO-2CD medium (Lonza) as described before (6). The F9 murine teratocarcinoma cells (American Type Culture Collection, ATCC; CRL-1720) were grown on 0.1% gelatin-coated tissue flasks in Dulbecco's Modified Eagle Medium (Gibco), supplemented with 10% FBS (Gibco), and incubated at 37 C in 5% CO 2 atmosphere.…”

Section: Methodsmentioning

confidence: 99%

“…The EDA-binding properties of SIP(F8)-SS-DM1 were analyzed by surface plasmon resonance (BIAcore 3000 System; GE Healthcare; Supplementary Fig. S4) on an EDA-coated CM5 sensor chip (BIAcore) as previously described (6).…”

Section: Adc Characterizationmentioning

confidence: 99%

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Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

et al. 2014

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It is generally thought that the anticancer efficacy of antibody-drug conjugates (ADC) relies on their internalization by cancer cells. However, recent work on an ADC that targets fibronectin in the tumor microenvironment suggests this may not be necessary. The alternatively spliced extra domains A and B (EDA and EDB) of fibronectin offer appealing targets for ADC development, because the antigen is strongly expressed in many solid human tumors and nearly undetectable in normal tissues except for the female reproductive system. In this study, we describe the properties of a set of ADCs based on an antibody targeting the alternatively spliced EDA of fibronectin coupled to one of a set of potent cytotoxic drugs (DM1 or one of two duocarmycin derivatives). The DM1 conjugate SIP(F8)-SS-DM1 mediated potent antitumor activity in mice bearing DM1-sensitive F9 tumors but not DM1-insensitive CT26 tumors. Quantitative biodistribution studies and microscopic analyses confirmed a preferential accumulation of SIP(F8)-SS-DM1 in the subendothelial extracellular matrix of tumors, similar to the pattern observed for unmodified antibody. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative and compatible with pharmaceutical development. Our findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that do not rely upon antigen internalization. Cancer Res; 74(9); 2569-78. Ó2014 AACR.

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Chemical and Genetic Modification

Farys¹,

Ginn²,

Badescu³

et al. 2013

Pharmaceutical Sciences Encyclopedia

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There are many natural post‐translational modifications of proteins (e.g., glycosylation, ubiquitination, acylation,and amino acid derivatization).Glycosylation is common for therapeutic proteins. Classes of proteins modified by glycosylation include monoclonal antibodies, blood factors, hematopoietic proteins, and cytokines. Excluding monoclonal antibodies, many proteins were, at least when they were first introduced to the clinic, designed to be used as a replacement protein for the corresponding endogenous protein. Maintaining control of the protein structure to be as close as possible to the structure of the endogeneous protein is therefore a key goal. In this review, we focus on (i) optimization of protein pharmacokinetics, (ii) improvement of protein properties to be used as medicines (this primarily includes reduction of immunogenic sequences and improvement of protein stability), (iii) addition of a therapeutic effect, and (iv) use of proteins as diagnostics.

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A Traceless Vascular‐Targeting Antibody–Drug Conjugate for Cancer Therapy

Cited by 31 publications

References 30 publications

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids

Chemical and Genetic Modification

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