Karen Veale
ImmunoGen, Inc.
AntigenMolecular biologyCytotoxic T cellAntibodyCell adhesion moleculeTripeptideChemistryBystander effectConjugateIn vitroImmunologyIn vivoCombinatorial chemistryDerivatizationMetaboliteSulfoneDipeptideMaytansinoidPeptideCamptothecinDrugExatecanLinkerMembrane permeabilityCancer researchAmino acidMonoclonal antibodyBiochemistryMetabolismStereochemistryCell cultureTurn (biochemistry)BiologyMicrosomeCancer cellPharmacology
8Publications
4H-index
61Citations
Publications 8
Newest
#1Juliet Costoplus (ImmunoGen, Inc.)H-Index: 4
#2Karen Veale (ImmunoGen, Inc.)H-Index: 4
Last. Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
view all 17 authors...
A new type of antibody–drug conjugate (ADC) has been prepared that contains a sulfur-bearing maytansinoid attached to an antibody via a highly stable tripeptide linker. Once internalized by cells, proteases in catabolic vesicles cleave the peptide of the ADC’s linker causing self-immolation that releases a thiol-bearing metabolite, which is then S-methylated. Conjugates were prepared with peptide linkers containing only alanyl residues, which were all l isomers or had a single d residue in one o...
7 CitationsSource
#1Wei Li (ImmunoGen, Inc.)H-Index: 3
#2Karen Veale (ImmunoGen, Inc.)H-Index: 4
Last. Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
view all 18 authors...
Antibody–drug conjugates (ADCs) that incorporate the exatecan derivative DXd in their payload are showing promising clinical results in solid tumor indications. The payload has an F-ring that also contains a second chiral center, both of which complicate its synthesis and derivatization. Here we report on new camptothecin-ADCs that do not have an F-ring in their payloads yet behave similarly to DXd-bearing conjugates in vitro and in vivo. This simplification allows easier derivatization of campt...
2 CitationsSource
#1Rajeeva Singh (ImmunoGen, Inc.)H-Index: 23
#2Yulius Setiady (ImmunoGen, Inc.)H-Index: 15
Last. Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
view all 22 authors...
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
#1Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
#2Jose F. Ponte (ImmunoGen, Inc.)H-Index: 10
Last. Ravi V. J. ChariH-Index: 30
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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
#1Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
#2Sharon D. Wilhelm (ImmunoGen, Inc.)H-Index: 10
Last. Ravi V. J. Chari (ImmunoGen, Inc.)H-Index: 30
view all 10 authors...
Several antibody–maytansinoid conjugates (AMCs) are in clinical trials for the treatment of various cancers. Each of these conjugates can be metabolized by tumor cells to give cytotoxic maytansinoid metabolites that can kill targeted cells. In preclinical studies in mice, the cytotoxic metabolites initially formed in vivo are further processed in the mouse liver to give several oxidized metabolic species. In this work, the primary AMC metabolites were synthesized and incubated with human liver m...
14 CitationsSource
#1Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
#2Joe Ponte (ImmunoGen, Inc.)
Last. Sharon D. Wilhelm (ImmunoGen, Inc.)H-Index: 10
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Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA A number of ADCs consisting of a maytansinoid cytotoxic agent linked to an antibody via a cleavable disulfide linker or a non-cleavable thioether linker are in the clinic. In preclinical models, antibody-maytansinoid conjugates (AMCs) utilizing a cleavable disulfide linker have been shown to be able to kill both the targeted antigen-positive (Ag+) cancer cells and also adjacent Ag- “bystander” cancer cells because of intra-cel...
Source
#1Rajeeva Singh (ImmunoGen, Inc.)H-Index: 23
#2Nathan Fishkin (ImmunoGen, Inc.)H-Index: 9
Last. Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
view all 16 authors...
Clinical-stage ADCs with a maytansinoid cytotoxic moiety (AMCs) currently use either a cleavable, hindered disulfide linker or the non-cleavable, thioether linker, SMCC. Both types of linkers have demonstrated comparative advantages pre-clinically for different cancer targets. Pre-clinically, benefits of the thioether linker can include greater AMC tolerability, while benefits of a hindered disulfide linker can include enhanced AMC activity. A goal of continued linker research is to create addit...
1 CitationsSource
#1Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
#2Sharon D. Wilhelm (ImmunoGen, Inc.)H-Index: 10
Last. Ravi V. J. Chari (ImmunoGen, Inc.)H-Index: 30
view all 9 authors...
Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Six antibody-maytansinoid conjugates (AMCs) consisting of the cytotoxic maytansinoid, DM1 or DM4, linked to a tumor-targeting monoclonal antibody are undergoing clinical evaluation, with the most advanced in Phase III testing. In these AMCs, the maytansinoid is attached through its C3 side chain to the antibody via a thioether or disulfide bond. The antibody moiety of the conjugate binds specifically to a tumor cell af...
1 CitationsSource