Antigen Shedding May Improve Efficiencies for Delivery of Antibody-Based Anticancer Agents in Solid Tumors

Abstract

Recombinant immunotoxins (RIT) are targeted anti-cancer agents that are composed of a targeting antibody fragment and a protein toxin fragment. SS1P is a RIT that targets mesothelin on the surface of cancer cells and is being evaluated in patients with mesothelioma. Mesothelin, like many other target antigens, is shed from the cell surface. However, whether antigen shedding positively or negatively affects the delivery of RIT remains unknown. In this study, we used experimental data with SS1P to develop a mathematical model that describes the relationship between tumor volume changes and the dose level of the administered RIT, while accounting for the potential effects of antigen shedding. We found that antigen shedding is a favorable biological process for targeted therapy of solid tumors. Shed antigens acted as a protective reservoir of RIT and buffered against the well-known binding site barrier effect, promoting a more uniform distribution of RIT in the tumor. In addition, our model reproduced the decrease in tumor size upon RIT treatment in animal experiments. Our findings therefore can be used to study the delivery efficacy of RITs and also antibody drug conjugates currently in clinical trials.

QSP Toolbox: Computational Implementation of Integrated Workflow Components for Deploying Multi-Scale Mechanistic Models

“…Third, many tumor-specific surface antigens are actively shed from cancer cells and shedding could potentially influence not only the tissue distribution of ADCs, with not only implications for safety (39)(40)(41), but also potentially the ability to permeate from tumor vessels by nature of the impact of the size of the complex (38). Shed antigen might also impact the ability of ADCs to bind their cellular targets in tumors (42,43). A QSP model can be used to integrate many of these complex, nonlinear, and unintuitive processes involved in the cellular and physiological disposition of ADCs and their components.…”

“…Several models have been proposed to mechanistically model ADC efficacy (43)(44)(45)(46)(47)(48)(49)(50)(51)(52), many of which have been previously reviewed (41). Mechanistic models have often been applied to investigate antibodies as a modality, although modeling studies focused on immunotoxins have also been reported (43,52).…”

“…Mechanistic models have often been applied to investigate antibodies as a modality, although modeling studies focused on immunotoxins have also been reported (43,52). It has also been suggested that ADCs are a special case of Baffinity^drug conjugates that can include alternate modalities to confer specificity (32,33), such as adnectins (53).…”

Selecting an Optimal Antibody for Antibody- Drug Conjugate Therapy

“…While it is generally thought that targets that are shed from the cell surface should be avoided for the development of ADCs, the clinical efficacy of Kadcyla (anti-HER2-ADC; Burris et al 2011) indicates that the presence of shed extracellular domain need not rule out an otherwise-promising ADC target. Indeed, a recent study suggests that the presence of soluble antigen may be beneficial for targeting solid tumors (Pak et al 2012). …”

Targeted Cancer Therapy: History and Development of Immunotoxins

“…The other reason for the failure of the IT in clinical trials is the fact that free mesothelin in circulation competes with membrane-associated mesothelin, for the IT. Hence, there is a sequestration of the IT by the circulating mesothelin, which reduces the effective concentration of the IT available to attack the tumors [94].…”