Targeting tumor and ocular angiogenesis via the VEGF and angiopoietin pathways : (VEGF ligands derived from CD11b+macrophages are critical for antigen clearance)

다국어 초록 (Multilingual Abstract)

VEGF-A is a prime responsible molecule for inducing tumor angiogenesis and metastasis. In comparison, angiopoietin is a supportive molecule in VEGF-A-induced tumor angiogenesis and metastasis. Therefore, double blockades of VEGF-A and angiopoietin could effectively to inhibit tumor angiogenesis, progression and metastasis. Here we designed novel molecule that can simultaneously block VEGF-A and angiopoietin by combination of minimal binding portion of VEGF-A in VEGFR1 and minimal binding portion of Ang2 in Tie2, and by connection with Fc portion of antibody IgG. We called this molecule as "double anti-angiogenic protein(DAAP)". Backbone of DAAP is structurally and functionally stable and effective for synchronous binding of VEGF-A and angiopoietin. DAAP is a highly effective molecule to reduce pathologic angiogenesis with having relatively high bioavailability, and can be potential therapeutic protein for blocking tumor and ocular angiogenesis.
Molecular and cellular mechanisms for antigen clearance from dermal tissue to draining lymph node(DLN) through peripheral lymphatic vessels are not well established. To investigate role of VEGF ligands on antigen clearance, we made a local dermal tissue inflammation mouse model by introduction of LPS from Gram- bacteria and LTA from Gram+ bacteria to ear skin of mouse. This model displayed profound lymphangiogenesis, marked infiltration of CD11b+ macrophages and increased antigen clearance in the local dermal tissue and its DLN. Depletion of CD11b+ macrophage by clodronate liposome and blockade of VEGF-A or VEGF-C by VEGF-Trap and sVEGFR3 substantially reduced LPS- and LTA-induced lymphangiogenesis, CD11b+ macrophage infiltration and antigen clearance, and local lymphatic flow in the local dermal tissue and its DLN. Taken together, we concluded that VEGF ligands derived from CD11b+ macrophages are critical for antigen clearance in the dermal tissue.