Emily E. Reid
ImmunoGen, Inc.
CytotoxicityCancerAntigenCytotoxic T cellAntibodyChemistryConjugateTherapeutic indexIn vitroIn vivoMechanism of actionMoietyTolerabilityDipeptidePeptideDimerDrugFolate receptorLinkerDNA CrosslinkingCancer researchDNABiochemistryStereochemistryCancer cellPharmacology
21Publications
4H-index
145Citations
Publications 21
Newest
#1Chen Bai (ImmunoGen, Inc.)H-Index: 6
#2Emily E. Reid (ImmunoGen, Inc.)H-Index: 4
Last. Nicholas C. Yoder (ImmunoGen, Inc.)H-Index: 15
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Antibody-drug conjugates have elicited great interest recently as targeted chemotherapies for cancer. Recent preclinical and clinical data have continued to raise questions about optimizing the design of these complex therapeutics. Biochemical methods for site-specific antibody conjugation have been a design feature of recent clinical ADCs, and preclinical reports suggest site-specifically conjugated ADCs generically offer improved therapeutic index (i.e., the fold difference between efficacious...
2 CitationsSource
#1Rajeeva Singh (ImmunoGen, Inc.)H-Index: 23
#2Emily E. Reid (ImmunoGen, Inc.)H-Index: 4
Last. Thomas A. Keating (ImmunoGen, Inc.)H-Index: 5
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The DNA-targeting indolinobenzodiazepine dimer (IGN) payloads are used in several clinical-stage antibody-drug conjugates (ADCs). IGN drugs alkylate DNA through the single imine moiety present in the dimer, in contrast to the pyrrolobenzodiazepine dimer (PBD) drugs, such as talirine and tesirine, which contain two imine moieties per dimer and are DNA cross-linking. This study explored the mechanism of binding of IGN to DNA in cells and to synthetic duplex and hairpin oligonucleotides. New, highl...
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#1Paulin Salomon (ImmunoGen, Inc.)H-Index: 6
#2Emily E. Reid (ImmunoGen, Inc.)H-Index: 4
Last. Rajeeva Singh (ImmunoGen, Inc.)H-Index: 23
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Although peptide linkers are used in multiple clinical-stage ADCs, there are only few reports on optimizing peptide linkers for efficient lysosomal proteolysis and for stability in circulation. We screened multiple dipeptide linkers for efficiency of proteolysis and compared them to the dipeptide linkers currently being evaluated in the clinic: Val-Cit, Val-Ala, and Ala-Ala. Lead dipeptide linkers selected from the initial screen were incorporated into ADCs with indolinobenzodiazepine dimer (IGN...
1 CitationsSource
#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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Abstract Antibody-drug conjugates (ADCs) incorporating potent indolinobenzodiazepine (IGN) DNA alkylators as the cytotoxic payload are currently undergoing clinical evaluation. The optimized design of these payloads consists of an unsymmetrical dimer possessing both an imine and an amine effectively eliminating DNA crosslinking and demonstrating improved tolerability in mice. Here we present an alternate approach to generating DNA alkylating ADCs by linking the IGN monomer with a biaryl system w...
2 CitationsSource
#1Katie E. Archer (ImmunoGen, Inc.)H-Index: 4
#2Emily E. Reid (ImmunoGen, Inc.)H-Index: 4
Last. Michael L. Miller (ImmunoGen, Inc.)H-Index: 17
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Indolinobenzodiazepine DNA alkylators (IGNs) are the cytotoxic payloads in antibody–drug conjugates (ADCs) currently undergoing Phase I clinical evaluation (IMGN779, IMGN632, and TAK164). These ADCs possess linkers that have been incorporated into a central substituted phenyl spacer. Here, we present an alternative strategy for the IGNs, linking through a carbamate at the readily available N-10 amine present in the monoimine containing dimer. As a result, we have designed a series of N-10 linked...
2 CitationsSource
#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
#1Michael L. MillerH-Index: 17
#2Emily E. ReidH-Index: 4
Last. Ravi V. J. ChariH-Index: 30
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#1Rajeeva SinghH-Index: 23
#2Luke HarrisH-Index: 5
Last. Thomas A. KeatingH-Index: 5
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Source
#1Laura A. Laviolette (ImmunoGen, Inc.)
Last. Dan SnellH-Index: 2
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DARPin® molecules are small engineered proteins, derived from natural ankyrin repeat proteins that are selected to bind to specific targets with high affinity. Individual DARPin® molecules can be linked together genetically in order to create multi-specific drug molecules. This versatility of DARPin® molecules makes them an attractive alternative to antibodies for the development of drug conjugates. We have developed DARPin® drug conjugates (DDCs) using a model EGFR multi-specific DARPin® molecu...
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#1Paulin Salomon (ImmunoGen, Inc.)H-Index: 6
#2Luke Harris (ImmunoGen, Inc.)H-Index: 5
Last. Rajeeva Singh (ImmunoGen, Inc.)H-Index: 23
view all 9 authors...
Peptides constitute a major linker class in antibody-drug conjugates (ADCs), designed to connect antibodies to cytotoxic drug molecules. An optimal linker for an ADC should be stable in circulation and be cleaved efficiently in lysosomes upon binding and internalization of the ADC in target cells, releasing drug molecules that exit lysosomes and inhibit key cellular functions. Previous studies have focused on a limited selection of peptide linkers and specific biochemical tools, such as a cathep...
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