Nathan Fishkin
ImmunoGen, Inc.
CytotoxicityAntigenCytotoxic T cellAntibodyChemistryConjugateIn vitroImmunologyIn vivoMechanism of actionMaytansinoidDrugLinkerCancer researchDNABiochemistryStereochemistryCell cultureCancer cellPharmacology
Publications 27
#1Emily E. Reid (ImmunoGen, Inc.)H-Index: 4
#2Katie E. Archer (ImmunoGen, Inc.)H-Index: 4
Last. Michael L. Miller (ImmunoGen, Inc.)H-Index: 17
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Antibody–drug conjugates (ADCs) that incorporate potent indolinobenzodiazepine DNA alkylators as the payload component are currently undergoing clinical evaluation. In one ADC design, the payload molecules are linked to the antibody through a peptidase-labile l-Ala-l-Ala linker. In order to determine the role of amino acid stereochemistry on antitumor activity and tolerability, we incorporated l- and d-alanyl groups in the dipeptide, synthesized all four diastereomers, and prepared and tested th...
2 CitationsSource
#1Zhengyang Jiang (A&M: Texas A&M University)H-Index: 5
#2Zhen Yang (Houston Methodist Hospital)H-Index: 12
Last. Kevin Burgess (A&M: Texas A&M University)H-Index: 83
view all 6 authors...
This study was undertaken to target cell surface receptors other than the ones typically associated with breast cancer {estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)}. It was also launched to use small molecules other than those most widely used for active targeting in general (e.g. folate and carbonic anhydrase IX ligands). Specifically, the focus of this study was on unique small molecules that bind the TrkC receptor, which is overexpre...
6 CitationsSource
#1Michael L. Miller (ImmunoGen, Inc.)H-Index: 17
#2Nathan Fishkin (ImmunoGen, Inc.)H-Index: 9
Last. Ravi V. J. Chari (ImmunoGen, Inc.)H-Index: 30
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The promise of tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, for cancer therapy. An ongoing challenge remains in identifying potent agents with alternative mechanisms of cell killing that can provide ADCs with high therapeutic indices and favorable tolerability. Here we describe the development of a new class of potent ...
50 CitationsSource
#1Luke HarrisH-Index: 5
#2Leanne LanieriH-Index: 8
Last. Nathan FishkinH-Index: 9
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Site-specific attachment of cell-killing agents to antibodies directed against tumor-associated antigens has continued to be an active area of innovation in the field of ADCs. Most reports focus on homogeneous ADCs that have a DAR (cytotoxic molecules per antibody ratio) of 2. Here we describe the preparation, biochemical characterization, and biological evaluation of ADCs made through conjugation of maytansinoids (DM1, DM4) to aldehydes derived from chemically oxidized N-terminal serines (SeriM...
#1Dilrukshi Vitharana (ImmunoGen, Inc.)H-Index: 2
#2Alan Wilhelm (ImmunoGen, Inc.)H-Index: 8
Last. Nathan Fishkin (ImmunoGen, Inc.)H-Index: 9
view all 14 authors...
Previously we have described the characterization of a proprietary class of indolino-benzodiazepine dimers, IGNs, with high potency against many cancer lines. Antibody-drug conjugates (ADCs) made with mono-imine containing IGNs were designed to only alkylate DNA and not cause DNA crosslinking. ADCs with the IGN linked via lysine residues of the antibody were shown to be highly potent and antigen specific. Here we apply our SeriMab site-specific technology platform, which employs N-terminal conju...
1 CitationsSource
#1Manami ShizukaH-Index: 4
#2Alan WilhelmH-Index: 8
Last. Michael L. MillerH-Index: 17
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#1Jose F. Ponte (ImmunoGen, Inc.)H-Index: 10
#2Xiuxia Sun (ImmunoGen, Inc.)H-Index: 6
Last. John M. Lambert (ImmunoGen, Inc.)H-Index: 52
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Antibody-drug conjugates (ADCs) have become a widely investigated modality for cancer therapy, in part due to the clinical findings with ado-trastuzumab emtansine (Kadcyla). Ado-trastuzumab emtansine utilizes the Ab-SMCC-DM1 format, in which the thiol-functionalized maytansinoid cytotoxic agent, DM1, is linked to the antibody (Ab) via the maleimide moiety of the heterobifunctional SMCC linker. The pharmacokinetic (PK) data for ado-trastuzumab emtansine point to a faster clearance for the ADC tha...
33 CitationsSource
#1Rajeeva Singh (ImmunoGen, Inc.)H-Index: 23
#2Yulius Setiady (ImmunoGen, Inc.)H-Index: 15
Last. Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
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A triglycyl peptide linker (CX) was designed for use in antibody-drug conjugates (ADCs), aiming to provide efficient release and lysosomal efflux of cytotoxic catabolites within targeted cancer cells. ADCs comprising anti-epithelial cell adhesion molecule (anti-EpCAM) and anti-epidermal growth factor receptor (anti-EGFR) antibodies with maytansinoid payloads were prepared using CX or a non-cleavable SMCC linker (CX and SMCC ADCs). The in vitro cytotoxic activities of CX and SMCC ADCs were simila...
15 CitationsSource
#1Watkins M Krystal (ImmunoGen, Inc.)H-Index: 1
#2Russell Walker (ImmunoGen, Inc.)H-Index: 3
Last. Angela Romanelli (ImmunoGen, Inc.)H-Index: 4
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IMGN779 is a CD33-targeting ADC consisting of a humanized anti-CD33 antibody, Z4681A, conjugated to DGN462, a novel DNA-alkylating agent, through a cleavable disulfide linker, sulfo-SPDB. CD33 is broadly expressed on leukemic blasts of patients with AML, making it a promising target for AML therapy. DGN462 is a member of the novel IGN class of DNA-acting cytotoxic agents, that consists of an indolino-benzodiazepine dimer containing a mono-imine moiety. Potent killing of AML tumor cells by DGN462...
13 CitationsSource
#1Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
#2Jose F. Ponte (ImmunoGen, Inc.)H-Index: 10
Last. Ravi V. J. ChariH-Index: 30
view all 21 authors...
Antibody anilino maytansinoid conjugates (AaMCs) have been prepared in which a maytansinoid bearing an aniline group was linked through the aniline amine to a dipeptide, which in turn was covalently attached to a desired monoclonal antibody. Several such conjugates were prepared utilizing different dipeptides in the linkage including Gly-Gly, l-Val-l-Cit, and all four stereoisomers of the Ala-Ala dipeptide. The properties of AaMCs could be altered by the choice of dipeptide in the linker. Each o...
16 CitationsSource