Development of potent monoclonal antibody auristatin conjugates for cancer therapy

Doronina, Svetlana O.; Toki, Brian E.; Torgov, Michael; Mendelsohn, Brian A.; Cerveny, Charles G.; Chace, Dana; DeBlanc, Ron L; Gearing, R Patrick; Bovee, Tim D.; Siegall, Clay B.; Francisco, Joseph A.; Wahl, Alan F.; Meyer, Damon L.; Senter, Peter D.

doi:10.1038/nbt832

Cited by 1,044 publications

(1,057 citation statements)

References 23 publications

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“…Some ADCs cured tumors in mice at doses of 0.5 -3 mg/Kg, while the same products could be administered at 60-fold greater dose with acceptable safety profiles [15]. Unfortunately, such a high therapeutic index is rarely observed in the clinic, suggesting that the tumor targeting properties of the antibody, the drug release process and/or the intrinsic sensitivity of tumor cells may be dramatically different in preclinical models and in cancer patients.…”

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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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: 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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“…Tested drugs included MMAE (microtubule‐disrupting agent),12, 13 SN‐38 (topoisomerase I inhibitor),14 etoposide (topoisomerase II inhibitor),15 cisplatin (DNA crosslinker),16 6‐MP (nucleotide analogue and inhibitor of RNA and protein synthesis)17, 18 and 5‐FU (pyrimidine analogue and thymidine synthase inhibitor) 18, 19. As we mentioned above, OVASC‐1 cells have been shown to be resistant to paclitaxel; therefore, we did not examine their sensitivity to this drug at the in vitro level to avoid redundancy.…”

Section: Resultsmentioning

confidence: 99%

A novel chemotherapeutic protocol for peritoneal metastasis and inhibition of relapse in drug resistant ovarian cancer

et al. 2018

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The majority of ovarian cancer patients are diagnosed in late stages of the disease, in which the tumor cells have leaked into the peritoneum and are present as tumorspheres. These tumorspheres are rich in cancer stem‐like cells (CSCs), which are resistant to therapy and are a major source of relapse. The purpose of this research was to identify a safe therapeutic approach that could eradicate the peritoneal CSC‐rich tumorspheres and inhibit relapse. Highly metastatic ascitic cells (OVASC‐1) that are resistant to standard‐of‐care chemotherapy due to upregulation of MDR1 gene were obtained from a patient with ovarian carcinoma and recurrent disease. CSC‐rich tumorspheres were generated, characterized, and treated with different chemotherapeutics. The most effective drug combination that could eradicate tumorspheres at nanomolar levels despite upregulation of MDR1 gene was identified. Luciferase‐expressing OVASC‐1 cells were implanted in the peritoneum of nude mice and treated with the identified drug combination. The progression of disease, response to therapy and recurrence were studied by quantitative imaging. Toxicity to abdominal tissues was studied by histopathology. Mice implanted with intraperitoneal (IP) OVASC‐1 xenografts showed limited response to combination therapy with cisplatin/paclitaxel at the maximum tolerated dose. Despite overexpression of MDR1 on OVASC‐1 cells, mice treated with our combination IP low‐dose MMAE and SN‐38 chemotherapy showed complete response without relapse. No signs of toxicity to abdominal tissues were observed. While MMAE and SN‐38 are not administered as free drugs due to their high potency and potential for systemic toxicity, our low‐dose localized therapy approach effectively restricted the cytotoxic effects to the tumor cells in the peritoneum. Consequently, maximum efficacy with minimal adverse effects was achieved. These remarkable results with IP low‐dose combination chemotherapy encourage investigation into its potential clinical application as either first‐line therapy or in cases of acquired resistance to cisplatin and paclitaxel.

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“…Acid-labile hydrazone linkers were among the first cleavable linkers used in ADCs. Upon internalization, the acidic pH in endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0) leads to hydrolysis of the hydrazone and subsequent release of the drug 2,20 . The serum stability of hydrazone linkers, however, is poor 21,22 .…”

Section: Linker Chemistriesmentioning

confidence: 99%

Antibody–Drug Conjugates for Tumor Targeting—Novel Conjugation Chemistries and the Promise of non-IgG Binding Proteins

et al. 2015

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Antibody-drug conjugates (ADCs) have emerged as a promising class of anti-cancer agents, combining the specificity of antibodies for tumor targeting and the destructive potential of highly potent drugs as payload. An essential component of these immunoconjugates is a bifunctional linker capable of reacting with the antibody and the payload to assemble a functional entity. Linker design is fundamental, as it must provide high stability in the circulation to prevent premature drug release, but be capable of releasing the active drug inside the target cell upon receptor-mediated endocytosis. Although ADCs have demonstrated an increased therapeutic window, compared to conventional chemotherapy in recent clinical trials, therapeutic success rates are still far from optimal. To explore other regimes of half-life variation and drug conjugation stoichiometries, it is necessary to investigate additional binding proteins which offer access to a wide range of formats, all with molecularly defined drug conjugation. Here, we delineate recent progress with site-specific and biorthogonal conjugation chemistries, and discuss alternative, biophysically more stable protein scaffolds like Designed Ankyrin Repeat Proteins (DARPins), which may provide such additional engineering opportunities for drug conjugates with improved pharmacological performance.3

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Development of potent monoclonal antibody auristatin conjugates for cancer therapy

Cited by 1,044 publications

References 23 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

A novel chemotherapeutic protocol for peritoneal metastasis and inhibition of relapse in drug resistant ovarian cancer

Antibody–Drug Conjugates for Tumor Targeting—Novel Conjugation Chemistries and the Promise of non-IgG Binding Proteins

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