title: Intracellular Released Payload Influences Potency and Bystander-Killing Effects of Antibody-Drug Conjugates in Preclinical Models.
abstract: Antibody-drug conjugates (ADC) comprise targeting antibodies armed with potent small-molecule payloads. ADCs demonstrate specific cell killing in clinic, but the basis of their antitumor activity is not fully understood. In this study, we investigated the degree to which payload release predicts ADC activity in vitro and in vivo ADCs were generated to target different receptors on the anaplastic large cell lymphoma line L-82, but delivered the same cytotoxic payload (monomethyl auristatin E, MMAE), and we found that the intracellular concentration of released MMAE correlated with in vitro ADC-mediated cytotoxicity independent of target expression or drug:antibody ratios. Intratumoral MMAE concentrations consistently correlated with the extent of tumor growth inhibition in tumor xenograft models. In addition, we developed a robust admixed tumor model consisting of CD30(+) and CD30(-) cancer cells to study how heterogeneity of target antigen expression, a phenomenon often observed in cancer specimens, affects the treatment response. CD30-targeting ADC delivering membrane permeable MMAE or pyrrolobenzodiazepine dimers demonstrated potent bystander killing of neighboring CD30(-) cells. In contrast, a less membrane permeable payload, MMAF, failed to mediate bystander killing in vivo, suggesting local diffusion and distribution of released payloads represents a potential mechanism of ADC-mediated bystander killing. Collectively, our findings establish that the biophysical properties and amount of released payloads are chief factors determining the overall ADC potency and bystander killing. Cancer Res; 76(9); 2710-9. ©2016 AACR.
authors.affiliation: Preclinical Science, Seattle Genetics, Inc., Bothell, Washington. fli@seagen.com.
authors.forename: Fu
authors.initials: F
authors.lastname: Li
authors.affiliation: Preclinical Science, Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Kim K
authors.initials: KK
authors.lastname: Emmerton
authors.affiliation: Translational Research, Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Jonas
authors.affiliation: Chemistry, Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Xinqun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Preclinical Science, Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Miyamoto
authors.affiliation: Chemistry, Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Jocelyn R
authors.initials: JR
authors.lastname: Setter
authors.affiliation: Experimental Pharmacology, Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Nicholas
authors.affiliation: Chemistry, Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Okeley
authors.affiliation: Chemistry, Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lyon
authors.affiliation: Translational Research, Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Benjamin
authors.affiliation: Preclinical Science, Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Che-Leung
authors.initials: CL
authors.lastname: Law
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D016503:Drug Delivery Systems / Q000379:methods; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007150:Immunohistochemistry; D008223:Lymphoma / Q000473:pathology; D013058:Mass Spectrometry; D051379:Mice; D016513:Mice, SCID; D009842:Oligopeptides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; C495575:monomethyl auristatin E