Quantitative Evaluation of the Effect of Antigen Expression Level on Antibody–Drug Conjugate Exposure in Solid Tumor

Bussing, David; Sharma, Sharad; Li, Zhe; Meyer, Lyndsey F.; Shah, Dhaval K.

doi:10.1208/s12248-021-00584-y

Cited by 16 publications

(14 citation statements)

References 35 publications

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“…Consequently, we inferred that it may be related to the drug target. Tumors with high expression of targeted antigen showed better effect when treated with ADC [37,38] or ICI. CD30 and PD-L1 is consistently overexpressed in patients with HL [39] [40] and signi cant in ammatory cell in ltration was detected in tumor samples.…”

Section: Discussionmentioning

confidence: 99%

Will antibody-drug conjugate and immune checkpoint inhibitor-based combination therapy close the gap between benefit and toxicity in the treatment of cancers? A systematic review and meta-analysis

Zhang

Yan

Chen

et al. 2023

Preprint

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Background Although antibody-drug conjugate (ADC) fosters hope for the treatment of cancer, the effect of single drug treatment is limited. Therefore, to achieve wider therapeutic effects, the combination of ADC and Immune checkpoint inhibitors (ICI) therapy may hold potential. Methods After literature retrieval, screening and data extraction, quality assessment was done by two investigators. Then, overall response rate (ORR) and adverse effects (AEs) were evaluated to study its efficiency and safety. Publication bias was also calculated through Funnel plot, Begg's Test and Egger's test. Meanwhile, heterogeneity was investigated through subgroup and sensitivity analysis. Results 11 eligible clinical studies with a total sample size of 551 were included. The pooled ORR was 59% (95% CI: 45% − 72%), especially in patients with relapsed classical Hodgkin lymphoma and patient treated with Brentuximab vedotin + Pembrolizumab. The most common AEs was peripheral neuropathy (38.2%) and AEs on skin (13.1% − 18.5%) and digestive system (8.7% − 28.1%) can not be overlooked. Conclusion ADC + ICI therapy may be recommended in cancer treatment, whereas strategies to manage toxicities warranted further exploration (PROSPERO CRD42023375601).

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Section: Discussionmentioning

confidence: 99%

Will antibody-drug conjugate and immune checkpoint inhibitor-based combination therapy close the gap between benefit and toxicity in the treatment of cancers? A systematic review and meta-analysis

Zhang

Yan

Chen

et al. 2023

Preprint

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“…Although ADC efficacy is usually related to antigen expression [ 7 ], clinical experience has enigmatically found little correlation of efficacy of SG with TROP2 expression levels [ 6 ]. Due to the rapid release of SN-38, the ADC has a short 14-h half-life in the systemic circulation while the concomitantly released hRS7 has a long 102-h half-life [ 2 ].…”

Section: Commentarymentioning

confidence: 99%

Could a Long-Acting Prodrug of SN-38 be Efficacious in Sacituzumab Govitecan-Resistant Tumors?

Santi,

Ashley,

Cabel

et al. 2024

BioDrugs

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We previously proposed that sacituzumab govitecan (SG, Trodelvy®) likely acts as a simple prodrug of systemic SN-38 as well as an antibody drug conjugate (ADC). In the present commentary, we assess whether a long-acting SN-38 prodrug, such as PLX038, might be efficacious in SG-resistant patients. We first describe possible mechanisms of action of SG, with new insights on pharmacokinetics and TROP2 receptor occupancy. We argue that SG is not an optimal conventional ADC and that the amount of systemic SN-38 spontaneously hydrolyzed from the ADC is so high it must have activity. Then, we describe the concept of time-over-target as related to the pharmacology of SG and PLX038 as SN-38 prodrugs. To be clear, we are not in any way suggesting that PLX038 or any SN-38 prodrug is superior to SG as an anticancer agent. Clearly, SG has the benefit over antigen-independent SN-38 prodrugs in that it targets cells with the TROP2 receptor. However, we surmise that PLX038 should be a more efficacious and less toxic prodrug of systemic SN-38 than SG. Finally, we suggest possible mechanisms of SG resistance and how PLX038 might perform in the context of each. Taken together, we argue that—contrary to many opinions—SG does not exclusively act as a conventional ADC, and propose that PLX038 may be efficacious in some settings of SG-resistance.

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“…For this purpose, NCI-N87, JIMT-1, Capan-1, and MDA-MB-468 xenografts characterized as high, medium, low, and very low antigen expressing, respectively, were utilized. 12,13 which was utilized to capture plasma and tumor PK incorporating an additional modeling component related to pharmacodynamic modulation. The model, successfully describing available data, has enabled the quantitative assessment of various system components and their contribution to the observed PK/ PD trends across a range of tumor types.…”

Section: How Might This Change Drug Discovery Development And/or Ther...mentioning

confidence: 99%

Quantitative evaluation of trastuzumab deruxtecan pharmacokinetics and pharmacodynamics in mouse models of varying degrees of HER2 expression

Vasalou,

Proia,

Kazlauskas

et al. 2024

CPT Pharmacom & Syst Pharma

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Trastuzumab deruxtecan (T‐DXd; DS‐8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)‐directed antibody drug conjugate (ADC) with demonstrated antitumor activity against a range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T‐DXd was administered in tumor‐bearing mice carrying NCI‐N87, Capan‐1, JIMT‐1, and MDA‐MB‐468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) of total antibody, T‐DXd, and released DXd and tumor concentrations of released DXd were evaluated, in addition to monitoring γΗ2AX and pRAD50 pharmacodynamic (PD) response. A positive relationship was observed between released DXd concentrations in tumor and HER2 expression, with NCI‐N87 xenografts characterized by the highest exposures compared to the remaining cell lines. γΗ2AX and pRAD50 demonstrated a sustained increase over several days occurring with a time delay relative to tumoral‐released DXd concentrations. In vitro investigations of cell‐based DXd disposition facilitated the characterization of DXd kinetics across tumor cells. These outputs were incorporated into a mechanistic mathematical model, utilized to describe PK/PD trends. The model captured plasma PK across dosing arms as well as tumor PK in NCI‐N87, Capan‐1, and MDA‐MB‐468 models; tumor concentrations in JIMT‐1 xenografts required additional parameter adjustments reflective of complex receptor dynamics. γΗ2AX longitudinal trends were well characterized via a unified PD model implemented across xenografts demonstrating the robustness of measured PD trends. This work supports the application of a mechanistic model as a quantitative tool, reliably projecting tumor payload concentrations upon T‐DXd administration, as the first step towards preclinical‐to‐clinical translation.

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Quantitative Evaluation of the Effect of Antigen Expression Level on Antibody–Drug Conjugate Exposure in Solid Tumor

Cited by 16 publications

References 35 publications

Will antibody-drug conjugate and immune checkpoint inhibitor-based combination therapy close the gap between benefit and toxicity in the treatment of cancers? A systematic review and meta-analysis

Will antibody-drug conjugate and immune checkpoint inhibitor-based combination therapy close the gap between benefit and toxicity in the treatment of cancers? A systematic review and meta-analysis

Could a Long-Acting Prodrug of SN-38 be Efficacious in Sacituzumab Govitecan-Resistant Tumors?

Quantitative evaluation of trastuzumab deruxtecan pharmacokinetics and pharmacodynamics in mouse models of varying degrees of HER2 expression

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