title: Chemical Structure and Concentration of Intratumor Catabolites Determine Efficacy of Antibody Drug Conjugates.
abstract: Despite recent technological advances in quantifying antibody drug conjugate (ADC) species, such as total antibody, conjugated antibody, conjugated drug, and payload drug in circulation, the correlation of their exposures with the efficacy of ADC outcomes in vivo remains challenging. Here, the chemical structures and concentrations of intratumor catabolites were investigated to better understand the drivers of ADC in vivo efficacy. Anti-CD22 disulfide-linked pyrrolobenzodiazepine (PBD-dimer) conjugates containing methyl- and cyclobutyl-substituted disulfide linkers exhibited strong efficacy in a WSU-DLCL2 xenograft mouse model, whereas an ADC derived from a cyclopropyl linker was inactive. Total ADC antibody concentrations and drug-to-antibody ratios (DAR) in circulation were similar between the cyclobutyl-containing ADC and the cyclopropyl-containing ADC; however, the former afforded the release of the PBD-dimer payload in the tumor, but the latter only generated a nonimmolating thiol-containing catabolite that did not bind to DNA. These results suggest that intratumor catabolite analysis rather than systemic pharmacokinetic analysis may be used to better explain and predict ADC in vivo efficacy. These are good examples to demonstrate that the chemical nature and concentration of intratumor catabolites depend on the linker type used for drug conjugation, and the potency of the released drug moiety ultimately determines the ADC in vivo efficacy.
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California zhang.donglu@gene.com.
authors.forename: Donglu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Keyang
authors.initials: K
authors.lastname: Xu
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Pillow
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Luna
authors.initials: L
authors.lastname: Liu
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Del Rosario
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Jintang
authors.initials: J
authors.lastname: He
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pei
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Sadowsky
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Hans K
authors.initials: HK
authors.lastname: Erickson
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.affiliation: Drug Metabolism and Pharmacokinetics (D.Z., Y.M., C.E.C.A.H, S.C.K.), Translational Oncology (S.Y., G.D.R.), BioAnalytical Sciences (K.X., L.L., J.H.), Discovery Chemistry (P.S.D., T.H.P., Z.P.), Protein Chemistry (J.D.S., H.K.E.), Genentech, South San Francisco, California.
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines