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Effect of antigen shedding on targeted delivery of immunotoxins in solid tumors from a mathematical model.

Pak Y, Pastan I, Kreitman RJ, Lee B - PLoS ONE (2014)

Bottom Line: Before a detailed numerical study, it was assumed that antigen shedding would reduce the efficacy of antibody-drug conjugates and immunotoxins.However, our previous study using a comprehensive mathematical model showed that antigen shedding can significantly improve the efficacy of the mesothelin-binding immunotoxin, SS1P (anti-mesothelin-Fv-PE38), and suggested that receptor shedding can be a general mechanism for enhancing the effect of inter-cellular signaling molecules.We show 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Institute of Functional Materials, Pusan National University, Busan, Republic of Korea; Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Most cancer-specific antigens used as targets of antibody-drug conjugates and immunotoxins are shed from the cell surface (Zhang & Pastan (2008) Clin. Cancer Res. 14: 7981-7986), although at widely varying rates and by different mechanisms (Dello Sbarba & Rovida (2002) Biol. Chem. 383: 69-83). Why many cancer-specific antigens are shed and how the shedding affects delivery efficiency of antibody-based protein drugs are poorly understood questions at present. Before a detailed numerical study, it was assumed that antigen shedding would reduce the efficacy of antibody-drug conjugates and immunotoxins. However, our previous study using a comprehensive mathematical model showed that antigen shedding can significantly improve the efficacy of the mesothelin-binding immunotoxin, SS1P (anti-mesothelin-Fv-PE38), and suggested that receptor shedding can be a general mechanism for enhancing the effect of inter-cellular signaling molecules. Here, we improved this model and applied it to both SS1P and another recombinant immunotoxin, LMB-2, which targets CD25. We show 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. 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, the slow shedding of CD25 is beneficial for LMB-2, for which the antigen is small in number and endocytosed slowly.

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Related in: MedlinePlus

Kinetic events involved in immunotoxin-antigen binding and intracellular trafficking.Each yellow arrow indicates a kinetic step of the model. The tumor cell sheds the surface antigen and the surface complexed antigen at a certain rate. The immunotoxin molecule exiting from the capillary diffuses in the extra-cellular space and binds to either the surface antigen or shed antigen by the association reaction between the antigen and immunotoxin. The surface-bound immunotoxin is internalized by the receptor-mediated endocytosis and mostly inactivated in the endosomal stage. The surviving toxin translocates to the cytosol, where the toxin inhibits protein synthesis and eventually causes cell death. In non-intoxicated cells, the antigen is replenished by fresh protein synthesis.
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pone-0110716-g006: Kinetic events involved in immunotoxin-antigen binding and intracellular trafficking.Each yellow arrow indicates a kinetic step of the model. The tumor cell sheds the surface antigen and the surface complexed antigen at a certain rate. The immunotoxin molecule exiting from the capillary diffuses in the extra-cellular space and binds to either the surface antigen or shed antigen by the association reaction between the antigen and immunotoxin. The surface-bound immunotoxin is internalized by the receptor-mediated endocytosis and mostly inactivated in the endosomal stage. The surviving toxin translocates to the cytosol, where the toxin inhibits protein synthesis and eventually causes cell death. In non-intoxicated cells, the antigen is replenished by fresh protein synthesis.

Mentions: The model consists mainly of two sets of partial differential equations (see Text S1 for detailed equations). One set of equations governs immunotoxin concentrations in the blood, in the extra-cellular space (ECS), and in the three compartments of the tumor cell: surface, endosome, and cytosol (Fig. 6). The other set of differential equations describes density changes of three different types of tumor cells (Fig. 7): un-intoxicated (type 1), intoxicated (type 2) and dead (type 3) cells. The un-intoxicated cells divide and shed their surface antigens into the ECS. They become intoxicated by the action of immunotoxin. Protein synthesis is arrested in intoxicated cells, which do not produce new antigen molecules and do not divide, but endocytosis, intracellular trafficking, and surface antigen shedding are still presumed to go on until the cells die. Only the antigen shedding and the on and off reactions of free immunotoxins with the surface antigens are still presumed to go on in the dead cells, which nonetheless occupy volume in the tumor mass until physically cleared. Tumor cells in each RU can move out of RU as the tumor cells increase in number by cell division or into RU as space is created when intoxicated cells die and get cleared. A simple flux consideration of the cell flow in and out of the RU gives the governing equation for tumor volume profile with time (Eq. 8 in Text S1).


Effect of antigen shedding on targeted delivery of immunotoxins in solid tumors from a mathematical model.

Pak Y, Pastan I, Kreitman RJ, Lee B - PLoS ONE (2014)

Kinetic events involved in immunotoxin-antigen binding and intracellular trafficking.Each yellow arrow indicates a kinetic step of the model. The tumor cell sheds the surface antigen and the surface complexed antigen at a certain rate. The immunotoxin molecule exiting from the capillary diffuses in the extra-cellular space and binds to either the surface antigen or shed antigen by the association reaction between the antigen and immunotoxin. The surface-bound immunotoxin is internalized by the receptor-mediated endocytosis and mostly inactivated in the endosomal stage. The surviving toxin translocates to the cytosol, where the toxin inhibits protein synthesis and eventually causes cell death. In non-intoxicated cells, the antigen is replenished by fresh protein synthesis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4208831&req=5

pone-0110716-g006: Kinetic events involved in immunotoxin-antigen binding and intracellular trafficking.Each yellow arrow indicates a kinetic step of the model. The tumor cell sheds the surface antigen and the surface complexed antigen at a certain rate. The immunotoxin molecule exiting from the capillary diffuses in the extra-cellular space and binds to either the surface antigen or shed antigen by the association reaction between the antigen and immunotoxin. The surface-bound immunotoxin is internalized by the receptor-mediated endocytosis and mostly inactivated in the endosomal stage. The surviving toxin translocates to the cytosol, where the toxin inhibits protein synthesis and eventually causes cell death. In non-intoxicated cells, the antigen is replenished by fresh protein synthesis.
Mentions: The model consists mainly of two sets of partial differential equations (see Text S1 for detailed equations). One set of equations governs immunotoxin concentrations in the blood, in the extra-cellular space (ECS), and in the three compartments of the tumor cell: surface, endosome, and cytosol (Fig. 6). The other set of differential equations describes density changes of three different types of tumor cells (Fig. 7): un-intoxicated (type 1), intoxicated (type 2) and dead (type 3) cells. The un-intoxicated cells divide and shed their surface antigens into the ECS. They become intoxicated by the action of immunotoxin. Protein synthesis is arrested in intoxicated cells, which do not produce new antigen molecules and do not divide, but endocytosis, intracellular trafficking, and surface antigen shedding are still presumed to go on until the cells die. Only the antigen shedding and the on and off reactions of free immunotoxins with the surface antigens are still presumed to go on in the dead cells, which nonetheless occupy volume in the tumor mass until physically cleared. Tumor cells in each RU can move out of RU as the tumor cells increase in number by cell division or into RU as space is created when intoxicated cells die and get cleared. A simple flux consideration of the cell flow in and out of the RU gives the governing equation for tumor volume profile with time (Eq. 8 in Text S1).

Bottom Line: Before a detailed numerical study, it was assumed that antigen shedding would reduce the efficacy of antibody-drug conjugates and immunotoxins.However, our previous study using a comprehensive mathematical model showed that antigen shedding can significantly improve the efficacy of the mesothelin-binding immunotoxin, SS1P (anti-mesothelin-Fv-PE38), and suggested that receptor shedding can be a general mechanism for enhancing the effect of inter-cellular signaling molecules.We show 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Institute of Functional Materials, Pusan National University, Busan, Republic of Korea; Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Most cancer-specific antigens used as targets of antibody-drug conjugates and immunotoxins are shed from the cell surface (Zhang & Pastan (2008) Clin. Cancer Res. 14: 7981-7986), although at widely varying rates and by different mechanisms (Dello Sbarba & Rovida (2002) Biol. Chem. 383: 69-83). Why many cancer-specific antigens are shed and how the shedding affects delivery efficiency of antibody-based protein drugs are poorly understood questions at present. Before a detailed numerical study, it was assumed that antigen shedding would reduce the efficacy of antibody-drug conjugates and immunotoxins. However, our previous study using a comprehensive mathematical model showed that antigen shedding can significantly improve the efficacy of the mesothelin-binding immunotoxin, SS1P (anti-mesothelin-Fv-PE38), and suggested that receptor shedding can be a general mechanism for enhancing the effect of inter-cellular signaling molecules. Here, we improved this model and applied it to both SS1P and another recombinant immunotoxin, LMB-2, which targets CD25. We show 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. 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, the slow shedding of CD25 is beneficial for LMB-2, for which the antigen is small in number and endocytosed slowly.

Show MeSH
Related in: MedlinePlus