Sela M

General

Full name : Michael Sela

First name : Michael

Mail : Department of Immunology, Weizmann Institute of Science, Rehovot 76100

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Country : Israel

Email : michael.sela@weizmann.ac.il

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References (4)

Title : Multimerization of ERBB2\/HER2 specific aptamer leads to improved receptor binding - Mahlknecht_2015_Biochem.Biophys.Res.Commun_465_218
Author(s) : Mahlknecht G , Maron R , Schechter B , Yarden Y , Sela M
Ref : Biochemical & Biophysical Research Communications , 465 :218 , 2015
Abstract : Aptamers represent a promising new treatment modality for cancer. Specificity and high affinity are two parameters that characterize aptamers. In this work, we elucidated physicochemical parameters of an ERBB2/HER2 specific aptamer and determined an optimal multimerization state, leading to higher binding and improved avidity. We applied biochemical, immunochemical and biophysical methodologies to characterize binding behaviors of multimerized versions of an ERBB2/HER2 specific aptamer and demonstrate structural integrity. Finally, we show that the trimeric ERBB2/HER2 specific aptamer instigates no immunogenic response in vivo. In summary, the set of methodologies we employed establishes a way to enhance activity of a model HER2-aptamer.
ESTHER : Mahlknecht_2015_Biochem.Biophys.Res.Commun_465_218
PubMedSearch : Mahlknecht_2015_Biochem.Biophys.Res.Commun_465_218
PubMedID: 26248137

Title : Inhibition of triple-negative breast cancer models by combinations of antibodies to EGFR - Ferraro_2013_Proc.Natl.Acad.Sci.U.S.A_110_1815
Author(s) : Ferraro DA , Gaborit N , Maron R , Cohen-Dvashi H , Porat Z , Pareja F , Lavi S , Lindzen M , Ben-Chetrit N , Sela M , Yarden Y
Ref : Proc Natl Acad Sci U S A , 110 :1815 , 2013
Abstract : Breast tumors lacking expression of human epidermal growth factor receptor 2 (HER2) and the estrogen and the progesterone receptors (triple negative; TNBC) are more aggressive than other disease subtypes, and no molecular targeted agents are currently available for their treatment. Because TNBC commonly displays EGF receptor (EGFR) expression, and combinations of monoclonal antibodies to EGFR effectively inhibit other tumor models, we addressed the relevance of this strategy to treatment of TNBC. Unlike a combination of the clinically approved monoclonal antibodies, cetuximab and panitumumab, which displaced each other and displayed no cooperative effects, several other combinations resulted in enhanced inhibition of TNBC's cell growth both in vitro and in animals. The ability of certain antibody mixtures to remove EGFR from the cell surface and to promote its intracellular degradation correlated with the inhibitory potential. However, unlike EGF-induced sorting of EGFR to lysosomal degradation, the antibody-induced pathway displayed independence from the intrinsic kinase activity and dimer formation ability of EGFR, and it largely avoided the recycling route. In conclusion, although TNBC clinical trials testing EGFR inhibitors reported lack of benefit, our results offer an alternative strategy that combines noncompetitive antibodies to achieve robust degradation of EGFR and tumor inhibition.
ESTHER : Ferraro_2013_Proc.Natl.Acad.Sci.U.S.A_110_1815
PubMedSearch : Ferraro_2013_Proc.Natl.Acad.Sci.U.S.A_110_1815
PubMedID: 23319610

Title : Aptamer to ErbB-2\/HER2 enhances degradation of the target and inhibits tumorigenic growth - Mahlknecht_2013_Proc.Natl.Acad.Sci.U.S.A_110_8170
Author(s) : Mahlknecht G , Maron R , Mancini M , Schechter B , Sela M , Yarden Y
Ref : Proc Natl Acad Sci U S A , 110 :8170 , 2013
Abstract : Aptamers, oligonucleotides able to avidly bind cellular targets, are emerging as promising therapeutic agents, analogous to monoclonal antibodies. We selected from a DNA library an aptamer specifically recognizing human epidermal growth factor receptor 2 (ErbB-2/HER2), a receptor tyrosine kinase, which is overexpressed in a variety of human cancers, including breast and gastric tumors. Treatment of human gastric cancer cells with a trimeric version (42 nucleotides) of the selected aptamer (14 nucleotides) resulted in reduced cell growth in vitro, but a monomeric version was ineffective. Likewise, when treated with the trimeric aptamer, animals bearing tumor xenografts of human gastric origin reflected reduced rates of tumor growth. The antitumor effect of the aptamer was nearly twofold stronger than that of a monoclonal anti-ErbB-2/HER2 antibody. Consistent with aptamer-induced intracellular degradation of ErbB-2/HER2, incubation of gastric cancer cells with the trimeric aptamer promoted translocation of ErbB-2/HER2 from the cell surface to cytoplasmic puncta. This translocation was associated with a lysosomal hydrolase-dependent clearance of the ErbB-2/HER2 protein from cell extracts. We conclude that targeting ErbB-2/HER2 with DNA aptamers might retard the tumorigenic growth of gastric cancer by means of accelerating lysosomal degradation of the oncoprotein. This work exemplifies the potential pharmacological utility of aptamers directed at cell surface proteins, and it highlights an endocytosis-mediated mechanism of tumor inhibition.
ESTHER : Mahlknecht_2013_Proc.Natl.Acad.Sci.U.S.A_110_8170
PubMedSearch : Mahlknecht_2013_Proc.Natl.Acad.Sci.U.S.A_110_8170
PubMedID: 23630281

Title : Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2\/ErbB-2 - Maron_2013_Proc.Natl.Acad.Sci.U.S.A_110_15389
Author(s) : Maron R , Schechter B , Mancini M , Mahlknecht G , Yarden Y , Sela M
Ref : Proc Natl Acad Sci U S A , 110 :15389 , 2013
Abstract : Due to intrinsic aggressiveness and lack of effective therapies, prognosis of pancreatic cancer remains dismal. Because the only molecular targeted drug approved for pancreatic ductal adenocarcinoma is a kinase inhibitor specific to the epidermal growth factor receptor (EGFR), and this receptor collaborates with another kinase, called HER2 (human EGF-receptor 2), we assumed that agents targeting EGFR and/or HER2 would effectively retard pancreatic ductal adenocarcinoma. Accordingly, two immunological strategies were tested in animal models: (i) two antibodies able to engage distinct epitopes of either EGFR or HER2 were separately combined, and (ii) pairs of one antibody to EGFR and another to HER2. Unlike the respective single monoclonal antibodies, which induced weak effects, both types of antibody combinations synergized in animals in terms of tumor inhibition. Immunological cooperation may not depend on receptor density, antigenic sites, or the presence of a mutant RAS protein. Nevertheless, both types of antibody combinations enhanced receptor degradation. Future efforts will examine the feasibility of each strategy and the potential of combining them to achieve sustained tumor inhibition.
ESTHER : Maron_2013_Proc.Natl.Acad.Sci.U.S.A_110_15389
PubMedSearch : Maron_2013_Proc.Natl.Acad.Sci.U.S.A_110_15389
PubMedID: 24003140