title: Statistical modeling of the drug load distribution on trastuzumab emtansine (Kadcyla), a lysine-linked antibody drug conjugate.
abstract: Trastuzumab emtansine (Kadcyla) is a recently approved antibody-drug conjugate produced by attachment of the anti-tubulin drug, DM1, to lysine amines via the SMCC linker. The resulting product exhibits a drug load distribution from 0 to 8 drugs per antibody that can be quantified using mass spectrometry. Different statistical models were tested against the experimental data derived from samples produced during process characterization studies to determine best fit. The Poisson distribution gives the best correlation for samples manufactured using the target process conditions (yielding the target average drug to antibody ratio (DAR) of 3.5) as well as those produced under conditions that exceed the allowed manufacturing ranges and yield products with average DAR values that are significantly different from the target (i.e., ≤3.0 or ≥4.0). The Poisson distribution establishes a link between average DAR values and drug load distributions, implying that measurement and control of the former (i.e., via a simple UV spectrophotometric method) could be used to indirectly control the latter in trastuzumab emtansine.
authors.affiliation: Departments of Protein Analytical Chemistry and ‡Biostatistics Genentech, Inc , South San Francisco, California 94080 United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Kim
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Joseph
authors.initials: J
authors.lastname: Marhoul
authors.forename: Fred
authors.initials: F
authors.lastname: Jacobson
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D008239:Lysine / Q000737:chemistry* / Q000378:metabolism; D008453:Maytansine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D015233:Models, Statistical; D015394:Molecular Structure; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008239:Lysine; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab