title: Engineered thio-trastuzumab-DM1 conjugate with an improved therapeutic index to target human epidermal growth factor receptor 2-positive breast cancer.
abstract: OBJECTIVE
  Antibody drug conjugates (ADCs) combine the ideal properties of both antibodies and cytotoxic drugs by targeting potent drugs to the antigen-expressing tumor cells, thereby enhancing their antitumor activity. Successful ADC development for a given target antigen depends on optimization of antibody selection, linker stability, cytotoxic drug potency, and mode of linker-drug conjugation to the antibody. Here, we systematically examined the in vitro potency as well as in vivo preclinical efficacy and safety profiles of a heterogeneous preparation of conventional trastuzumab-mcc-DM1 (TMAb-mcc-DM1) ADC with that of a homogeneous engineered thio-trastuzumab-mpeo-DM1 (thioTMAb-mpeo-DM1) conjugate.
  
  
  RESULTS
  To generate thioTMAb-mpeo-DM1, one drug maytansinoid 1 (DM1) molecule was conjugated to an engineered cysteine residue at Ala114 (Kabat numbering) on each trastuzumab-heavy chain, resulting in two DM1 molecules per antibody. ThioTMAb-mpeo-DM1 retained similar in vitro anti-cell proliferation activity and human epidermal growth factor receptor 2 (HER2) binding properties to that of the conventional ADC. Furthermore, it showed improved efficacy over the conventional ADC at DM1-equivalent doses (μg/m(2)) and retained efficacy at equivalent antibody doses (mg/kg). An improved safety profile of >2-fold was observed in a short-term target-independent rat safety study. In cynomolgus monkey safety studies, thioTMAb-mpeo-DM1 was tolerated at higher antibody doses (up to 48 mg/kg or 6,000 μg DM1/m(2)) compared with the conventional ADC that had dose-limiting toxicity at 30 mg/kg (6,000 μg DM1/m(2)).
  
  
  CONCLUSIONS
  The engineered thioTMAb-mpeo-DM1 with broadened therapeutic index represents a promising antibody drug conjugate for future clinical development of HER2-positive targeted breast cancer therapies.
authors.affiliation: Genentech, Inc., South San Francisco, California 94080, USA. jagath@gene.com
authors.forename: Jagath R
authors.initials: JR
authors.lastname: Junutula
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Flagella
authors.forename: Richard A
authors.initials: RA
authors.lastname: Graham
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Parsons
authors.forename: Edward
authors.initials: E
authors.lastname: Ha
authors.forename: Helga
authors.initials: H
authors.lastname: Raab
authors.forename: Sunil
authors.initials: S
authors.lastname: Bhakta
authors.forename: Trung
authors.initials: T
authors.lastname: Nguyen
authors.forename: Debra L
authors.initials: DL
authors.lastname: Dugger
authors.forename: Guangmin
authors.initials: G
authors.lastname: Li
authors.forename: Elaine
authors.initials: E
authors.lastname: Mai
authors.forename: Gail D
authors.initials: GD
authors.lastname: Lewis Phillips
authors.forename: Hajime
authors.initials: H
authors.lastname: Hiraragi
authors.forename: Reina N
authors.initials: RN
authors.lastname: Fuji
authors.forename: Jay
authors.initials: J
authors.lastname: Tibbitts
authors.forename: Richard
authors.initials: R
authors.lastname: Vandlen
authors.forename: Susan D
authors.initials: SD
authors.lastname: Spencer
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scheller
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D008453:Maytansine / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D013438:Sulfhydryl Compounds; D000068878:Trastuzumab