Michael L. Miller
ImmunoGen, Inc.
CytotoxicityAntigenCytotoxic T cellAntibodyChemistryConjugateTherapeutic indexIn vitroIn vivoCombinatorial chemistryMechanism of actionPaclitaxelTaxoidDrugFolate receptorLinkerCancer researchDNABiochemistryStereochemistryCancer cellPharmacology
61Publications
17H-index
1,494Citations
Publications 50
Newest
#1Jose F. PonteH-Index: 10
#2Leanne LanieriH-Index: 8
Last. Greg M. Thurber (UM: University of Michigan)H-Index: 23
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Several antibody-drug conjugates (ADCs) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRα). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react with normal tissue in animal models used to test efficacy (typically mice), and the impact o...
1 CitationsSource
#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
view all 7 authors...
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#1Leanne Lanieri (ImmunoGen, Inc.)H-Index: 8
#2Rassol Laleau (ImmunoGen, Inc.)H-Index: 3
Last. Richard Gregory (ImmunoGen, Inc.)H-Index: 1
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Antibody-drug conjugates (ADCs) are designed to deliver a potent cytotoxic payload directly to tumors, thus limiting exposure in normal tissues. However, target antigen expression on normal tissues can lead to lower systemic ADC exposures, resulting in sub-efficacious concentrations at the tumor site as well as heterogeneous distribution within tumors. Traditional preclinical efficacy studies performed in rodent models using ADCs with non-cross-reactive antibodies have been of limited translatio...
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