A Mechanistic Tumor Penetration Model to Guide Antibody Drug Conjugate Design

Vasalou, Christina; Helmlinger, Gabriel; Gomes, Bruce
March 2015
PLoS ONE;Mar2015, Vol. 10 Issue 3, p1
Academic Journal
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.


Related Articles

  • Research & Markets: Competitor Analysis: Antibody-Drug Conjugates (ADC).  // Biomedical Market Newsletter;12/14/2011, Vol. 21, p1 

    The article focuses on the "Competitor Analysis: Antibody-Drug Conjugates (ADC)" report released from Research & Markets Ltd. The report provides information on the current projects in research and development of antibody-drug conjugates and other immunoconjugates in oncology including drug...

  • Internalization, Trafficking, Intracellular Processing and Actions of Antibody-Drug Conjugates. Xu, Shi // Pharmaceutical Research;Nov2015, Vol. 32 Issue 11, p3577 

    Purpose: This review discusses the molecular mechanism involved in the targeting and delivery of antibody-drug conjugates (ADCs), the new class of biopharmaceuticals mainly designed for targeted cancer therapy. Methods: this review goes over major progress in preclinical and clinical studies of...

  • Let-7d Inhibits Growth and Metastasis in Breast Cancer by Targeting Jab1/Cops5. Wei, Yongchang; Liu, Guohong; Wu, Balu; Yuan, Yufen; Pan, Yunbao // Cellular Physiology & Biochemistry (Karger AG);Jul2018, Vol. 47 Issue 5, p2126 

    Background/Aims: MicroRNAs (miRNAs) regulate the expressions of cancer-related genes, and are involved in the development and progression of various human cancers. Here, we performed further analyses to determine whether let-7d is functionally linked to Jab1 in breast cancer....

  • Circulating Tumor Cells as a Biomarker of Response to Treatment in Patient-Derived Xenograft Mouse Models of Pancreatic Adenocarcinoma. Torphy, Robert J.; Tignanelli, Christopher J.; Kamande, Joyce W.; Moffitt, Richard A.; Herrera Loeza, Silvia G.; Soper, Steven A.; Yeh, Jen Jen // PLoS ONE;Feb2014, Vol. 9 Issue 2, p1 

    Circulating tumor cells (CTCs) are cells shed from solid tumors into circulation and have been shown to be prognostic in the setting of metastatic disease. These cells are obtained through a routine blood draw and may serve as an easily accessible marker for monitoring treatment effectiveness....

  • Affibody-DyLight Conjugates for In Vivo Assessment of HER2 Expression by Near-Infrared Optical Imaging. Zielinski, Rafal; Hassan, Moinuddin; Lyakhov, Ilya; Needle, Danielle; Chernomordik, Victor; Garcia-Glaessner, Alejandra; Ardeshirpour, Yasaman; Capala, Jacek; Gandjbakhche, Amir // PLoS ONE;Jul2012, Vol. 7 Issue 7, p1 

    Purpose: Amplification of the HER2/neu gene and/or overexpression of the corresponding protein have been identified in approximately 20% of invasive breast carcinomas. Assessment of HER2 expression in vivo would advance development of new HER2-targeted therapeutic agents and, potentially,...

  • Monoclonal Antibody Conjugation via Chemical Modification.  // BioPharm International;Dec2003, Vol. 16 Issue 12, p32 

    This article focuses on the research in conjugation of monoclonal antibodies for therapeutic purposes. It primarily discusses the experimental design, protocols, and procedures for the preparation of in vivo therapeutic drug conjugates, such as the conjugation of monoclonal antibodies to other...

  • The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma. Huynh, Chanh; Poliseno, Laura; Segura, Miguel F.; Medicherla, Ratna; Haimovic, Adele; Menendez, Silvia; Shulian Shang; Pavlick, Anna; Yongzhao Shao; Darvishian, Farbod; Boylan, John F.; Osman, Iman; Hernando, Eva // PLoS ONE;2011, Vol. 6 Issue 9, p1 

    Several reports have demonstrated a role for aberrant NOTCH signaling in melanoma genesis and progression, prompting us to explore if targeting this pathway is a valid therapeutic approach against melanoma. We targeted NOTCH signaling using RO4929097, a novel inhibitor of gamma secretase, which...

  • Establishment of Human Patient-Derived Endometrial Cancer Xenografts in NOD scid Gamma Mice for the Study of Invasion and Metastasis. Unno, Kenji; Ono, Masanori; Winder, Abigail D.; Maniar, Kruti P.; Paintal, Ajit S.; Yu, Yanni; Wei, Jian-Jun; Lurain, John R.; Kim, J. Julie // PLoS ONE;Dec2014, Vol. 9 Issue 12, p1 

    Objective: Most endometrial cancers are detected early and have a good prognosis, while some endometrial cancers are highly invasive, metastasize early, and respond suboptimally to therapy. Currently, appropriate model systems to study the aggressive nature of these tumors are lacking. The...

  • miR-143 Overexpression Impairs Growth of Human Colon Carcinoma Xenografts in Mice with Induction of Apoptosis and Inhibition of Proliferation. Borralho, Pedro M.; Simõ es, André E. S.; Gomes, Sofia E.; Lima, Raquel T.; Carvalho, Tâ nia; Ferreira, Duarte M. S.; Vasconcelos, Maria H.; Castro, Rui E.; Rodrigues, Cecília M. P. // PLoS ONE;2011, Vol. 6 Issue 8, p1 

    Background: MicroRNAs (miRNAs) are aberrantly expressed in human cancer and involved in the (dys)regulation of cell survival, proliferation, differentiation and death. Specifically, miRNA-143 (miR-143) is down-regulated in human colon cancer. In the present study, we evaluated the role of...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics