Simulating the Selection of Resistant Cells with Bystander Killing and Antibody Coadministration in Heterogeneous Human Epidermal Growth Factor Receptor 2–Positive Tumors

Menezes, Bruna; Linderman, Jennifer J.; Thurber, Greg M.

doi:10.1124/dmd.121.000503

Cited by 12 publications

(7 citation statements)

References 53 publications

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“…With the two approved HER2 ADCs, T-DXd monotherapy shows stronger efficacy than T-DM1, which benefits from higher dosing and payload bystander effects 46 . Bystander effects provide some improvements against the binding site barrier 20,47 , but tissue penetration has been shown to be important even with bystander payloads. 17,36 Therefore, increased penetration in the high expression model further improved T-DXd efficacy.…”

Section: Discussionmentioning

confidence: 99%

In vivoAuto-tuning of Antibody-Drug Conjugate Delivery for Effective Immunotherapy using High-Avidity, Low-Affinity Antibodies

Kopp,

Dong,

Kwon

et al. 2024

Preprint

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Antibody-drug conjugates (ADCs) have experienced a surge in clinical approvals in the past five years. Despite this success, a major limitation to ADC efficacy in solid tumors is poor tumor penetration, which leaves many cancer cells untargeted. Increasing antibody doses or co-administering ADC with an unconjugated antibody can improve tumor penetration and increase efficacy when target receptor expression is high. However, it can also reduce efficacy in low-expression tumors where ADC delivery is limited by cellular uptake. This creates an intrinsic problem because many patients express different levels of target between tumors and even within the same tumor. Here, we generated High-Avidity, Low-Affinity (HALA) antibodies that can automatically tune the cellular ADC delivery to match the local expression level. Using HER2 ADCs as a model, HALA antibodies were identified with the desired HER2 expression-dependent competitive binding with ADCsin vitro. Multi-scale distribution of trastuzumab emtansine and trastuzumab deruxtecan co-administered with the HALA antibody were analyzedin vivo, revealing that the HALA antibody increased ADC tumor penetration in high-expression systems with minimal reduction in ADC uptake in low-expression tumors. This translated to greater ADC efficacy in immunodeficient mouse models across a range of HER2 expression levels. Furthermore, Fc-enhanced HALA antibodies showed improved Fc-effector function at both high and low expression levels and elicited a strong response in an immunocompetent mouse model. These results demonstrate that HALA antibodies can expand treatment ranges beyond high expression targets and leverage strong immune responses.

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Section: Discussionmentioning

confidence: 99%

In vivoAuto-tuning of Antibody-Drug Conjugate Delivery for Effective Immunotherapy using High-Avidity, Low-Affinity Antibodies

Kopp,

Dong,

Kwon

et al. 2024

Preprint

Self Cite

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“…Expanding the agent-based model to quantify the effectiveness of antibody co-administration and bystander killing 16 Recently, Menezes et al extended their hybrid agentbased model described above to incorporate angiogenesis, heterogeneous receptor expression, heterogeneous tumor cell sensitivity to payloads, and bystander effects (for payloads that can diffuse to surrounding cells). 16 Using this model, the researchers investigated the effectiveness of co-administration of unconjugated trastuzumab and ADC (for T-DM1 and T-MMAE), as well as bystander killing (for T-MMAE only). Simulations using this model showed both T-DM1 and T-MMAE benefitted from antibody co-administration, including in tumors with intrinsic resistance to the payload.…”

Section: Spatial Effectsmentioning

confidence: 99%

“…Recently, Menezes et al extended their hybrid agent‐based model described above to incorporate angiogenesis, heterogeneous receptor expression, heterogeneous tumor cell sensitivity to payloads, and bystander effects (for payloads that can diffuse to surrounding cells) 16 . Using this model, the researchers investigated the effectiveness of co‐administration of unconjugated trastuzumab and ADC (for T‐DM1 and T‐MMAE), as well as bystander killing (for T‐MMAE only).…”

Section: Development Of Systems Pharmacology Modelsmentioning

confidence: 99%

Development of and insights from systems pharmacology models of antibody‐drug conjugates

Lam

Reddy

Ball

et al. 2022

CPT Pharmacom & Syst Pharma

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Antibody‐drug conjugates (ADCs) have gained traction in the oncology space in the past few decades, with significant progress being made in recent years. Although the use of pharmacometric modeling is well‐established in the drug development process, there is an increasing need for a better quantitative biological understanding of the pharmacokinetic and pharmacodynamic relationships of these complex molecules. Quantitative systems pharmacology (QSP) approaches can assist in this endeavor; recent computational QSP models incorporate ADC‐specific mechanisms and use data‐driven simulations to predict experimental outcomes. Various modeling approaches and platforms have been developed at the in vitro, in vivo, and clinical scales, and can be further integrated to facilitate preclinical to clinical translation. These new tools can help researchers better understand the nature and mechanisms of these targeted therapies to help achieve a more favorable therapeutic window. This review delves into the world of systems pharmacology modeling of ADCs, discussing various modeling efforts in the field thus far.

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“…Similar to PK analysis, this evaluation of the chemical reaction kinetics of nanoparticles has sparked a debate on the effectiveness of drug release systems such as lysosomal-mediated drug release via sulfide bond in tumor pathology and DDS. 8,9 Chemical reaction rate analysis necessitates in vitro experiments and frequent sampling using the stopped-flow method. 10 Substituting PK assessment with frequent blood sampling to detect blood retention is comparatively straightforward.…”

Section: ■ Introductionmentioning

confidence: 99%

Pharmacokinetic–Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity

Yamashita,

Imanishi,

Ueki

et al. 2024

Mol. Pharmaceutics

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This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic−pharmacodynamic (PK−PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth−time profiles. An intratumoral threshold concentration of DOX (55−64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK−PD analysis of the tumor growth−time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK−PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.

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Simulating the Selection of Resistant Cells with Bystander Killing and Antibody Coadministration in Heterogeneous Human Epidermal Growth Factor Receptor 2–Positive Tumors

Cited by 12 publications

References 53 publications

In vivoAuto-tuning of Antibody-Drug Conjugate Delivery for Effective Immunotherapy using High-Avidity, Low-Affinity Antibodies

In vivoAuto-tuning of Antibody-Drug Conjugate Delivery for Effective Immunotherapy using High-Avidity, Low-Affinity Antibodies

Development of and insights from systems pharmacology models of antibody‐drug conjugates

Pharmacokinetic–Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity

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