Immunotoxin therapy of cancer

Pastan, Ira; Hassan, Raffit; FitzGerald, David J.; Kreitman, Robert J.

doi:10.1038/nrc1891

Cited by 470 publications

(424 citation statements)

References 58 publications

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“…An attractive and highly potent class of payloads is immunotoxins; hybrid proteins composed of an affinity recognition moiety (often an antibody fragment) and a toxic domain derived from plant or bacterial toxins [49]. Pseudomonas exotoxin A is a well characterized bacterial protein toxin with proven therapeutic efficacy in numerous pre-clinical models as well as in clinical trials.…”

Section: Targeting Payloadsmentioning

confidence: 99%

Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications

et al. 2010

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a b s t r a c tAffibody molecules are a class of engineered affinity proteins with proven potential for therapeutic, diagnostic and biotechnological applications. Affibody molecules are small (6.5 kDa) single domain proteins that can be isolated for high affinity and specificity to any given protein target. Fifteen years after its discovery, the Affibody technology is gaining use in many groups as a tool for creating molecular specificity wherever a small, engineering compatible tool is warranted. Here we summarize recent results using this technology, propose an Affibody nomenclature and give an overview of different HER2-specific Affibody molecules. Cumulative evidence suggests that the three helical scaffold domain used as basis for these molecules is highly suited to create a molecular affinity handle for vastly different applications.

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Section: Targeting Payloadsmentioning

confidence: 99%

Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications

et al. 2010

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“…Alternatively, mesothelin can be targeted with antibody-drug conjugates (ADC) combining the specificity of an antibody with the potency of a toxophore. Antibodies conjugated to various toxophores have shown potent antitumor activity in preclinical animal models (23). Recently, encouraging clinical efficacy has been observed with SAR3419 targeting CD19 (24).…”

Section: Introductionmentioning

confidence: 99%

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

Golfier

Kopitz

Kahnert

et al. 2014

Molecular Cancer Therapeutics

199

166

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Mesothelin is a tumor differentiation antigen frequently overexpressed in tumors such as mesothelioma, ovarian, pancreatic, and lung adenocarcinomas while showing limited expression in nonmalignant tissues. Mesothelin is therefore an attractive target for cancer therapy using antibody-drug conjugates (ADC). This study describes the detailed characterization of anetumab ravtansine, here referred to as BAY 94-9343, a novel ADC consisting of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker. Binding properties of the anti-mesothelin antibody were analyzed using surface plasmon resonance, immunohistochemistry, flow cytometry, and fluorescence microscopy. Effects of BAY 94-9343 on cell proliferation were first studied in vitro and subsequently in vivo using subcutaneous, orthotopic, and patient-derived xenograft tumor models. The antibody binds to human mesothelin with high affinity and selectivity, thereby inducing efficient antigen internalization. In vitro, BAY 94-9343 demonstrated potent and selective cytotoxicity of mesothelin-expressing cells with an IC 50 of 0.72 nmol/L, without affecting mesothelin-negative or nonproliferating cells. In vivo, BAY 94-9343 localized specifically to mesothelin-positive tumors and inhibited tumor growth in both subcutaneous and orthotopic xenograft models. In addition, BAY 94-9343 was able to induce a bystander effect on neighboring mesothelin-negative tumor cells. Antitumor efficacy of BAY 94-9343 correlated with the amount of mesothelin expressed and was generally superior to that of standard-of-care regimen resulting in complete tumor eradication in most of the models. BAY 94-9343 is a selective and highly potent ADC, and our data support its development for the treatment of patients with mesothelin-expressing tumors. Mol Cancer Ther; 13(6); 1537-48. Ó2014 AACR.

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“…cancer treatment | immunotherapy | leukemia | mesothelioma | protein engineering M any mAbs have been developed for cancer treatment, but few of these are clinically useful as single agents because they do not efficiently kill those cells (1). Instead, antibodies of this type can be used as carriers for cytotoxic drugs, radioisotopes, or protein toxins (2).…”

mentioning

confidence: 99%

Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes

Liu

Onda

Lee

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

144

140

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Recombinant immunotoxins (RITs) are hybrid proteins used to treat cancer. These proteins are composed of an Fv that reacts with cancer cells joined to a portion of Pseudomonas exotoxin A, which kills the cell. Because the toxin is a foreign protein, it can induce neutralizing antibodies and thereby limit the number of doses a patient can receive. We previously identified seven major mouse B-cell epitopes in the toxin, and subsequently silenced them using point mutations that converted large hydrophilic amino acids to alanine, yet retained full antitumor activity. Here we present results in which we identify and silence human B-cell epitopes in the RIT HA22. We obtained B cells from patients with antibodies to RITs, isolated the corresponding variable fragments (Fvs), and constructed a phage-display library containing Fvs that bind to the RITs. We then used alanine scanning mutagenesis to locate the epitopes. We found that human and mouse epitopes frequently overlap but are not identical. Most mutations that remove mouse epitopes did not remove human epitopes. Using the epitope information, we constructed a variant immunotoxin, HA22-LR-LO10, which has low reactivity with human antisera, yet has high cytotoxic and antitumor activity and can be given to mice at high doses without excess toxicity. The toxin portion of this RIT (LR-LO10) can be used with Fvs targeting other cancer antigens and is suitable for clinical development.cancer treatment | immunotherapy | leukemia | mesothelioma | protein engineering

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Immunotoxin therapy of cancer

Cited by 470 publications

References 58 publications

Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications

Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes

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