title: A mechanistic tumor penetration model to guide antibody drug conjugate design.
abstract: Antibody drug conjugates (ADCs) represent novel anti-cancer modalities engineered to specifically target and kill tumor cells expressing corresponding antigens. Due to their large size and their complex kinetics, these therapeutic agents often face heterogeneous distributions in tumors, leading to large untargeted regions that escape therapy. We present a modeling framework which includes the systemic distribution, vascular permeability, interstitial transport, as well as binding and payload release kinetics of ADC-therapeutic agents in mouse xenografts. We focused, in particular, on receptor dynamics such as endocytic trafficking mechanisms within cancer cells, to simulate their impact on tumor mass shrinkage upon ADC administration. Our model identified undesirable tumor properties that can impair ADC tissue homogeneity, further compromising ADC success, and explored ADC design optimization scenarios to counteract upon such unfavorable intrinsic tumor tissue attributes. We further demonstrated the profound impact of cytotoxic payload release mechanisms and the role of bystander killing effects on tumor shrinkage. This model platform affords a customizable simulation environment which can aid with experimental data interpretation and the design of ADC therapeutic treatments.
authors.affiliation: Advanced Quantitative Sciences, Novartis, Cambridge, MA, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Vasalou
authors.affiliation: Advanced Quantitative Sciences, Novartis, Cambridge, MA, United States of America.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Helmlinger
authors.affiliation: Advanced Quantitative Sciences, Novartis, Cambridge, MA, United States of America.
authors.forename: Bruce
authors.initials: B
authors.lastname: Gomes
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D015195:Drug Design; D006801:Humans; D018796:Immunoconjugates / Q000378:metabolism / Q000627:therapeutic use*; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018796:Immunoconjugates