Walter A. Blattler
ImmunoGen, Inc.
Binding siteCytotoxicityPharmacokineticsImmunotoxinAntigenMolecular biologyCytotoxic T cellAntibodyChemistryConjugateImmunologyIn vivoRicinImmunoconjugateMaytansinoidGeloninLectinGalactose bindingMonoclonal antibodyBiochemistryMedicineBiologyPharmacology
Publications 58
#1Gail Lewis Phillips (Genentech)H-Index: 26
#2Guangmin LiH-Index: 13
Last. Mark X. SliwkowskiH-Index: 70
view all 17 authors...
HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and to...
1,696 CitationsSource
#1Wayne C. Widdison (ImmunoGen, Inc.)H-Index: 15
#2Sharon D. WilhelmH-Index: 10
Last. Ravi V. J. ChariH-Index: 30
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Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clinical trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent we...
383 CitationsSource
#1Hans K. Erickson (ImmunoGen, Inc.)H-Index: 17
#2Peter U. ParkH-Index: 5
Last. Walter A. BlattlerH-Index: 36
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Antibody-drug conjugates are targeted anticancer agents consisting of a cytotoxic drug covalently linked to a monoclonal antibody for tumor antigen–specific activity. Once bound to the target cell-surface antigen, the conjugate must be processed to release an active form of the drug, which can reach its intracellular target. Here, we used both biological and biochemical methods to better define this process for antibody-maytansinoid conjugates. In particular, we examined the metabolic fate in ce...
655 CitationsSource
#1Yelena Kovtun (ImmunoGen, Inc.)H-Index: 19
#2Charlene AudetteH-Index: 14
Last. Victor S. GoldmacherH-Index: 55
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Conjugates of the anti-CanAg humanized monoclonal antibody huC242 with the microtubule-formation inhibitor DM1 (a maytansinoid), or with the DNA alkylator DC1 (a CC1065 analogue), have been evaluated for their ability to eradicate mixed cell populations formed from CanAg-positive and CanAg-negative cells in culture and in xenograft tumors in mice. We found that in culture, conjugates of either drug killed not only the target antigen-positive cells but also the neighboring antigen-negative cells....
426 CitationsSource
#1Hongsheng Xie (ImmunoGen, Inc.)H-Index: 7
#2Walter A. Blattler (ImmunoGen, Inc.)H-Index: 36
It is a commonly held belief that most treatments for disseminated cancers are only moderately effective because the agents lack cell-killing mechanisms that act specifically on cancer cells. In antibody–drug conjugates, such nonspecific cytotoxic agents are combined with exquisitely specific monoclonal antibodies that bind to tumour-associated antigens and, thus, get endowed with new pharmacological characteristics. Not only is their activity newly targeted towards tumours and tumour cells, whi...
28 CitationsSource
#1Lintao Wang (ImmunoGen, Inc.)H-Index: 8
#2Godfrey W. Amphlett (ImmunoGen, Inc.)H-Index: 5
Last. Wei Zhang (ImmunoGen, Inc.)H-Index: 115
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Immunoconjugates are being explored as novel cancer therapies with the promise of target-specific drug delivery. The immunoconjugate, huN901–DM1, composed of the humanized monoclonal IgG1 antibody, huN901, and the maytansinoid drug, DM1, is being tested in clinical trials to treat small cell lung carcinoma (SCLC). huN901–DM1 contains an average of three to four DM1 drug molecules per huN901 antibody molecule. The drug molecules are linked to huN901 through random modification of huN901 at e-amin...
321 CitationsSource
#1Lintao Wang (ImmunoGen, Inc.)H-Index: 8
#2Godfrey W. Amphlett (ImmunoGen, Inc.)H-Index: 5
Last. Wei Zhang (ImmunoGen, Inc.)H-Index: 115
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Purpose. The aim of this study was to perform structural characterization of a recombinant monoclonal antibody (MAb), huN901, by electrospray time-of-flight mass spectrometry (ESI-TOFMS) using both "top-down" and "bottom-up" approaches. Methods. In the top-down approach, the molecular masses of the deglycosylated huN901 and the light and heavy chains of the antibody were measured by direct infusion MS and liquid chromatography-mass spectrometry (LC-MS). In the bottom-up approach, trypsin and Asp...
109 CitationsSource
#1Alexandru C. Lazar (ImmunoGen, Inc.)H-Index: 15
#2Lintao Wang (ImmunoGen, Inc.)H-Index: 8
Last. Wei Zhang (ImmunoGen, Inc.)H-Index: 115
view all 6 authors...
Recombinant monoclonal antibody drug products play an increasingly important role in the treatment of various diseases. Antibodies are large, multi-chain proteins and antibody preparations often contain several molecular variants, which renders them heterogeneous. The heterogeneity is further increased in immunoconjugates prepared by covalently linking several drug molecules per antibody molecule. As part of the product characterization, the molecular weights of the antibodies or their drug conj...
150 CitationsSource
The humanized monoclonal antibody maytansinoid conjugate, cantuzumab mertansine (huC242-DM1) that contains on average three to four linked drug molecules per antibody molecule was evaluated in CD-1 mice for its pharmacokinetic behavior and tissue distribution, and the results were compared with those of the free antibody huC242. The pharmacokinetics in blood were similar for 125I-labeled conjugate and antibody with terminal half-lives of 154 and 156 h, respectively. Pharmacokinetic analysis usin...
198 CitationsSource
#1Erin K. Maloney (ImmunoGen, Inc.)H-Index: 9
Last. Rajeeva SinghH-Index: 23
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An antagonistic monoclonal antibody, designated EM164, has been developed which binds specifically to the human insulin-like growth factor I receptor (IGF-IR) and inhibits the proliferation and survival functions of the receptor in cancer cells. EM164 was initially selected by a rapid cell-based screen of hybridoma supernatants to identify antibodies that bind to IGF-IR but not to the homologous insulin receptor and that show maximal inhibition of IGF-I-stimulated autophosphorylation of IGF-IR. ...
490 Citations