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A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor.

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Presentation on theme: "A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor."— Presentation transcript:

1 A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor microenvironment by Wei Zhang, Suying Dang, Tao Hong, Jian Tang, Jing Fan, Dawei Bu, Yanjie Sun, Zhugang Wang, and Thomas Wisniewski Blood Volume 120(14): October 4, 2012 ©2012 by American Society of Hematology

2 Schema of antiplatelet GPIIIa49-66 scFv Ab (A11) properties for the inhibition of tumor metastasis.
Schema of antiplatelet GPIIIa49-66 scFv Ab (A11) properties for the inhibition of tumor metastasis. (A) Summary figure. Events occurring following tumor intravasation, tumor-platelet-endothelial cell binding and platelet-tumor thrombus formation, tumor-platelet embolization, angiogenesis, and extravasation. T indicates tumor cells; and AP, activated platelets. (B) Platelets promoting metastases in an experimental pulmonary metastasis B16 tumor model. (Top row) Lung specimens with metastastic colonies. Plt indicates platelet. (Bottom row) Numeric results of surface pulmonary nodules (n = 8, **P < .01). (C) Hypothesized mechanisms of A11 on the inhibition of tumor metastasis by lysing activated platelets within the tumor microenvironment. Wei Zhang et al. Blood 2012;120: ©2012 by American Society of Hematology

3 Effect of A11 on spontaneous metastasis of LLC
Effect of A11 on spontaneous metastasis of LLC. (A) It illustrates the treatment protocols in the spontaneous lung metastasis model. Effect of A11 on spontaneous metastasis of LLC. (A) It illustrates the treatment protocols in the spontaneous lung metastasis model. LLC indicates Lewis lung carcinoma. (B) Mean number of surface nodules per lung. (C) Mean volume of nodules per lung. (D) Representative histologic evidence from tumor sections of the different groups. (i-ii) 13CG2. (i) ×40; (ii) ×200. (iii-iv) A11. (iii) ×40; (iv) × CG2 indicates control scFv Ab; n = 8, *P < .01. Wei Zhang et al. Blood 2012;120: ©2012 by American Society of Hematology

4 Effect of A11 on experimental metastasis of LLC
Effect of A11 on experimental metastasis of LLC. (A) The (i-ii) preventive and (iii-v) therapeutic protocols in a lung metastasis model are shown. i.v. indicates intravenous injection; and LLC, Lewis lung carcinoma. Effect of A11 on experimental metastasis of LLC. (A) The (i-ii) preventive and (iii-v) therapeutic protocols in a lung metastasis model are shown. i.v. indicates intravenous injection; and LLC, Lewis lung carcinoma. (B) Mean number of surface nodules per lung in the different treatments. (C) Mean volume of nodules per lung in the different treatment groups. Ctrl. indicates control scFv Ab 13CG2; n = 8/group, **P < .001, *P < .01. Wei Zhang et al. Blood 2012;120: ©2012 by American Society of Hematology

5 The pathophysiologic relevance of the platelet GPIIIa49-66 epitope (GP49) on experimental lung metastases of B16 melanoma. The pathophysiologic relevance of the platelet GPIIIa49-66 epitope (GP49) on experimental lung metastases of B16 melanoma. Mice were treated as described in “Experimental lung metastasis assay.” At day 21, mice were killed. (A) Mean number of surface nodules per lung. (B) Mean volume of nodules per lung. (C) Induction of platelet count drop was determined at different time points. n = 8. *Values with significant differences. n.s. indicates no significant difference. Wei Zhang et al. Blood 2012;120: ©2012 by American Society of Hematology

6 Effect of A11 on early invasion of B16 melanoma cells in lung tissue.
Effect of A11 on early invasion of B16 melanoma cells in lung tissue. (A) Frozen slide of lung tissue (×20) observed under a fluorescence microscope. (B) Quantitative result of adhesion of B16 in lung tissue as measurements of fluorescent intensity under a fluorescence plate reader. n = 5; *P < .01. Wei Zhang et al. Blood 2012;120: ©2012 by American Society of Hematology

7 Molecular mechanisms by which A11 inhibits tumor metastasis.
Molecular mechanisms by which A11 inhibits tumor metastasis. (A-B) Effect of A11 on the adhesion of tumor cells to platelets in vitro. (A) The adhesion of LLCs to activated platelets as observed under fluorescence microscope. (B) The quantitative analysis of adhesion of LLC with activated platelet in the presence of various concentration of A11, as measurements of fluorescent intensity under a fluorescence plate reader. The experiment was repeated 3 times and each concentration had 4 wells. (C) Effect of A11 on the adhesion of platelets to HUVECs in vitro. The extent of adhesion was expressed as the percentage of control platelets adhering without preincubation with A11 or control scFv (13CG2). The experiment was repeated 3 times and each concentration had 4 wells. (D-E) Effect of A11 on platelet-mediated tumor cell adhesion to endothelial cell in vitro. B16 melanoma cells adhesion to HUVECs was performed as described in “Assay of tumor cells adhesion to endothelial cells.” (D) The adhesion efficiency of B16 tumor cell was observed under a fluorescence microscope. (E) Quantitative result of adhesion of B16 melanoma cells with HUVECs. (F) Effect of A11 on the destruction of already formed tumor platelet aggregates. Data and SD are given for 3 separate experiments at 0.5μM reagent in which each time point represents 5 measurements. Wei Zhang et al. Blood 2012;120: ©2012 by American Society of Hematology

8 Effect of A11 on the viability of tumor cells and endothelial cells in vitro and in vivo.
Effect of A11 on the viability of tumor cells and endothelial cells in vitro and in vivo. (A-C) Effect of A11 on the viability of (A) B16, (B) LLC, and (C) HUVECs as evaluated by the MTT assay. Data are mean ± SD of 3 different determinations. (D) Effect of A11 on the chemotaxis of tumor cells and HUVECs. Chemotaxis was performed in Transwell plates as described in “Transwell migration assay.” Data and SD are given for 3 independent experiment results in which each concentration represent 4 measurements. (E) Effect of A11 on the s.c. tumor growth. Tumor dimensions were measured with calipers for calculation of tumor volume. n = 5; error bars indicate SD. Wei Zhang et al. Blood 2012;120: ©2012 by American Society of Hematology

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