Quantifying ADC bystander payload penetration with cellular resolution using pharmacodynamic mapping

Khera, Eshita; Cilliers, Cornelius; Smith, Michael D.; Ganno, Michelle L.; Lai, Katharine C.; Keating, Thomas A.; Kopp, Anna; Nessler, Ian; Abu-Yousif, Adnan O.; Thurber, Greg M.

doi:10.1016/j.neo.2020.12.001

Cited by 32 publications

(16 citation statements)

References 62 publications

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“…Understanding and integrating all spatial dynamics that describe intratumoral micro-pharmacokinetics, although experimentally and computationally intensive, can refine the proposed model. The impact of intratumoral drug distribution is a critical issue that contributes to varied local pharmacodynamic responses to small molecule inhibitors 73 and antibody-drug conjugates 74 , 75 .…”

Section: Discussionmentioning

confidence: 99%

Maximizing response to intratumoral immunotherapy in mice by tuning local retention

et al. 2022

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Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.

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Section: Discussionmentioning

confidence: 99%

Maximizing response to intratumoral immunotherapy in mice by tuning local retention

et al. 2022

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“…Toxicities associated with Rova-T treatment, including pleural and pericardial effusions, may be caused in part by the pyrrolobenzodiazepine component of the antibody-drug conjugate. While the mechanism is not fully understood, studies suggest that systemic release or bystander effect may be involved [22][23][24] . Systemic release occurs when premature cleavage of the linker results in the release of the drug into circulation, causing off-target toxicities.…”

Section: Discussionmentioning

confidence: 99%

A phase I/II study of rovalpituzumab tesirine in delta-like 3—expressing advanced solid tumors

et al. 2021

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Delta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.

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“…Three previously validated computational models of increasing complexity 30 – 32 were used to describe the cellular, tissue, and in vivo impact of HALA antibody properties. The first model is a bivalent competition kinetic model used to measure HALA antibody competition versus the ADC on a cell monolayer.…”

Section: Methodsmentioning

confidence: 99%

Design of high avidity and low affinity antibodies for in situ control of antibody drug conjugate targeting

Evans

Thurber

2022

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Antibody-Drug Conjugates (ADCs) have rapidly expanded in the clinic, with 7 new approvals in 3 years. For solid tumors, high doses of ADCs improve tissue penetration and efficacy. These doses are enabled by lower drug-to-antibody ratios and/or co-administration of unconjugated antibody carrier doses to avoid payload toxicity. While effective for highly expressed targets, these strategies may not maintain efficacy with lower target expression. To address this issue, a carrier dose that adjusts binding in situ according to cellular expression was designed using computational modeling. Previous studies demonstrated that coadministration of unconjugated antibody with the corresponding ADC at an 8:1 ratio improves ADCs efficacy in high HER2 expressing tumors. By designing a High Avidity, Low Affinity (HALA) carrier antibody, ADC binding is partially blocked in high expression cells, improving tissue penetration. In contrast, the HALA antibody cannot compete with the ADC in low expressing cells, allowing ADC binding to the majority of receptors. Thus, the amount of competition from the carrier dose automatically adjusts to expression levels, allowing tailored competition between different patients/metastases. The computational model highlights two dimensionless numbers, the Thiele modulus and a newly defined competition number, to design an optimal HALA antibody carrier dose for any target.

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Quantifying ADC bystander payload penetration with cellular resolution using pharmacodynamic mapping

Cited by 32 publications

References 62 publications

Maximizing response to intratumoral immunotherapy in mice by tuning local retention

Maximizing response to intratumoral immunotherapy in mice by tuning local retention

A phase I/II study of rovalpituzumab tesirine in delta-like 3—expressing advanced solid tumors

Design of high avidity and low affinity antibodies for in situ control of antibody drug conjugate targeting

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