A mechanistic tumor penetration model to guide antibody drug conjugate design.
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 l...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4364906?pdf=render |
| _version_ | 1828329729985347584 |
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| author | Christina Vasalou Gabriel Helmlinger Bruce Gomes |
| author_facet | Christina Vasalou Gabriel Helmlinger Bruce Gomes |
| author_sort | Christina Vasalou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T20:29:36Z |
| format | Article |
| id | doaj.art-a630c1e966174de5a03c02792062b4b3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T20:29:36Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a630c1e966174de5a03c02792062b4b32022-12-22T02:31:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01103e011897710.1371/journal.pone.0118977A mechanistic tumor penetration model to guide antibody drug conjugate design.Christina VasalouGabriel HelmlingerBruce GomesAntibody 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.http://europepmc.org/articles/PMC4364906?pdf=render |
| spellingShingle | Christina Vasalou Gabriel Helmlinger Bruce Gomes A mechanistic tumor penetration model to guide antibody drug conjugate design. PLoS ONE |
| title | A mechanistic tumor penetration model to guide antibody drug conjugate design. |
| title_full | A mechanistic tumor penetration model to guide antibody drug conjugate design. |
| title_fullStr | A mechanistic tumor penetration model to guide antibody drug conjugate design. |
| title_full_unstemmed | A mechanistic tumor penetration model to guide antibody drug conjugate design. |
| title_short | A mechanistic tumor penetration model to guide antibody drug conjugate design. |
| title_sort | mechanistic tumor penetration model to guide antibody drug conjugate design |
| url | http://europepmc.org/articles/PMC4364906?pdf=render |
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