title: Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates.
abstract: Antibody drug conjugates (ADCs) are a therapeutic class offering promise for cancer therapy. The attachment of cytotoxic drugs to antibodies can result in an effective therapy with better safety potential than nontargeted cytotoxics. To understand the role of conjugation site, we developed an enzymatic method for site-specific antibody drug conjugation using microbial transglutaminase. This allowed us to attach diverse compounds at multiple positions and investigate how the site influences stability, toxicity, and efficacy. We show that the conjugation site has significant impact on ADC stability and pharmacokinetics in a species-dependent manner. These differences can be directly attributed to the position of the linkage rather than the chemical instability, as was observed with a maleimide linkage. With this method, it is possible to produce homogeneous ADCs and tune their properties to maximize the therapeutic window.
authors: Rinat-Pfizer, 230 East Grand Avenue, South San Francisco, CA 94080, USA. pavel.strop@pfizer.com
authors: Pavel
authors: P
authors: Strop
authors: Shu-Hui
authors: SH
authors: Liu
authors: Magdalena
authors: M
authors: Dorywalska
authors: Kathy
authors: K
authors: Delaria
authors: Russell G
authors: RG
authors: Dushin
authors: Thomas-Toan
authors: TT
authors: Tran
authors: Wei-Hsien
authors: WH
authors: Ho
authors: Santiago
authors: S
authors: Farias
authors: Meritxell Galindo
authors: MG
authors: Casas
authors: Yasmina
authors: Y
authors: Abdiche
authors: Dahui
authors: D
authors: Zhou
authors: Ramalakshmi
authors: R
authors: Chandrasekaran
authors: Caroline
authors: C
authors: Samain
authors: Carole
authors: C
authors: Loo
authors: Andrea
authors: A
authors: Rossi
authors: Mathias
authors: M
authors: Rickert
authors: Stellanie
authors: S
authors: Krimm
authors: Teresa
authors: T
authors: Wong
authors: Sherman Michael
authors: SM
authors: Chin
authors: Jessica
authors: J
authors: Yu
authors: Jeanette
authors: J
authors: Dilley
authors: Javier
authors: J
authors: Chaparro-Riggers
authors: Gary F
authors: GF
authors: Filzen
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Fang
authors: F
authors: Wang
authors: Jeremy S
authors: JS
authors: Myers
authors: Jaume
authors: J
authors: Pons
authors: David L
authors: DL
authors: Shelton
authors: Arvind
authors: A
authors: Rajpal
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry* / Q000276:immunology; D000970:Antineoplastic Agents / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D051381:Rats; D011503:Transglutaminases / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D050257:Tubulin Modulators; D011503:Transglutaminases