Antigen Shedding and Targeted Delivery of Immunotoxins in Solid Tumors: A Mathematical Model

Cells modulate responses to signals in the extracellular environment by shedding cell surface antigens. Understanding this process is important because antibody-based anti-cancer therapies target cell surface antigens. This process affects tumor responses to this type of therapy.

In an article published in the December 15, 2008 issues of Clinical Cancer Research, Yujian Zhang and Ira Pastan at the Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, described that the concentration of the tumor antigen mesothelin, a tumor differentiation antigen that is normally present on the mesothelial cells lining the pleura, peritoneum and pericardium, is extremely high within the interstitial space of tumors, where it can block antibody action. They also showed that the concentration of shed mesothelin within the tumor is lowered by chemotherapy.[1]

This observation, they believed, may have important implications for the successful treatment of solid tumors by antibody-drug conjugates and whole antibodies. But to date, it’s still poorly understood why many cancer-specific antigens are shed and how the shedding affects delivery efficiency of antibody-based protein drugs. For a long time scientists assumed that antigen shedding would reduce the efficacy of antibody-drug conjugates and immunotoxins.

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Mathematical model
However, Youngshang Pak at the Department of Chemistry and Institute of Functional Materials, Pusan National University, Busan, Republic of Korea and Ira Pastan, Robert J. Kreitman, Byungkook Lee at the Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland, showed that by using a comprehensive mathematical model antigen shedding can significantly improve the efficacy of SS1P, a recombinant immunotoxin, composed of an antimesothelin Fv fused to a 38 kDa fragment of Pseudomonas exotoxin A. SSPI targets mesothelin, a cell surface glycoprotein that is highly expressed in many cancers including malignant mesothelioma.[2]

In their study, Pak et al. 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 antibody-drug conjugate, while accounting for the potential effects of antigen shedding

The scientists suggested that receptor shedding can be a general mechanism for enhancing the effect of inter-cellular signaling molecules.

New study
Now, in a new study, published in Plos One (October 24, 2014) Pak and his colleagues improved their model and applied it to both SS1P and another recombinant immunotoxin, LMB-2 (anti-Tac(Fv)-PE38), an anti-CD25 recombinant immunotoxin that contains an antibody Fv fragment fused to truncated Pseudomonas exotoxin. In this study, they showed that the effect of antigen shedding is influenced by a number of factors including the number of antigen molecules on the cell surface and the endocytosis rate. [2][3]

The scientists concluded that the high shedding rate of mesothelin is beneficial for SS1P, for which the antigen is large in number and endocytosed rapidly. On the other hand, they determined that slow shedding of CD25 is beneficial for LMB-2, for which the antigen is small in number and endocytosed slowly.