US-12617848-B2 - Methods of treating ocular pathologies using bifunctional molecules that target growth factors

Abstract

This invention relates to pharmaceutical compositions and methods for treatment of ophthalmic or ocular diseases and conditions. The compositions contain targeting molecules that are made up of a bifunctional hepatoma-derived growth factor-specific antibody covalently attached to a trapper that specifically binds vascular endothelial growth factor and/or transforming growth factor beta. Specific eye conditions that can be beneficially affected by the compositions and methods of the invention include age-related macular degeneration, diabetic retinopathy, peripheral vitreoretinopathy, and retinal vein occlusion.

Inventors

• Li Mao
• Hening Ren

Assignees

• UNIVERSITY OF MARYLAND, BALTIMORE

Dates

Publication Date

20260505

Application Date

20211108

Claims (5)

1. 1 . A pharmaceutical composition comprising a bifunctional hepatoma-derived growth factor (HDGF)-vascular endothelial growth factor (VEGF) trapper antibody-based targeting protein and a pharmaceutically acceptable carrier, wherein the targeting protein comprises an HDGF-binding antibody binding site, and a receptor domain which specifically binds to VEGF, wherein the targeting protein comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 17 and a light chain variable domain comprising the sequence of SEQ ID NO: 18, and wherein the receptor domain is connected to the C-terminus of the heavy chain.
2. 2 . The pharmaceutical composition of claim 1 , wherein the VEGF is selected from the group consisting of VEGF-A, VEGF-B, and VEGF-C.
3. 3 . The pharmaceutical composition of claim 1 , wherein the targeting protein comprises a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 20.
4. 4 . The pharmaceutical composition of claim 1 , wherein the targeting protein comprises a chain comprising the sequence of SEQ ID NO: 4 and a light chain comprising the sequence of SEQ ID NO: 20.
5. 5 . The pharmaceutical composition of claim 1 , wherein the targeting protein comprises two chains comprising the sequence of SEQ ID NO: 4 and two light chains comprising the sequence of SEQ ID NO: 20.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of Ser. No. 16/325,764 filed Feb. 15, 2019, which is a 371 national stage application of PCT Application No. PCT/US2017/046934, filed Aug. 15, 2017, and claims benefit of Provisional Application No. 62/375,894, filed Aug. 16, 2016, the entire contents of each of which are hereby incorporated by reference as if fully set forth herein, under 35 U.S.C. § 119(e). REFERENCE TO SEQUENCE LISTING SUBMITTED VIA EFS-WEB This application includes an electronically submitted sequence listing in .txt format. The .txt file contains a sequence listing entitled “2021-06-15_15024-342US1_ST25.txt” created on Jun. 15, 2021 and is 60,512 bytes in size. The sequence listing contained in this .txt file is part of the specification and is hereby incorporated by reference herein in its entirety. BACKGROUND 1. Field of the Invention The invention relates to the field of medicine and pharmacology. In particular, the invention relates to an ophthalmic pharmaceutical composition including a bifunctional hepatoma-derived growth factor (HDGF)-vascular endothelial growth factor (VEGF) trapper antibody-based targeting protein, and a method for using this composition and a method for treating ophthalmic pathologies such as diabetic retinopathy, age-related macular degeneration, neovasular age-related macular degeneration, peripheral vitreoretinopathy, retinal vein occlusion, and the like. 2. Background of the Invention Lung diseases including lung cancer and pulmonary fibrosis (PF) are a leading cause of death worldwide. PF is one of a family of related diseases called interstitial lung diseases that can result in lung scarring. As the lung tissue becomes scarred, it interferes with a person's ability to breathe. Hyperproliferation of cells (e.g., fibroblasts or cancer cells) can cause various types of medical conditions (i.e., hyperproliferative conditions) such as keloids, idiopathic pulmonary fibrosis, and lung cancer. Keloids are a type of abnormally formed scar which is composed mainly of collagen as a result of an overgrowth of fibroblasts during wound healing. While keloid scars are benign and not contagious, it may be accompanied by severe itchiness, pain, and changes in skin texture. On the other hand, interstitial lung diseases, particularly idiopathic pulmonary fibrosis, are life threatening and have no cure currently. Hepatoma-derived growth factor (HDGF) is a heparin-binding growth factor identified from media conditioned by a human hepatoma-derived cell line. It produces mitogenic activity in various cells types. Normally, HDGF is highly expressed during embryonic development in smooth muscle, gut, and endothelium, but not after birth. It has also been implicated in angiogenesis. High-level HDGF is observed in various human cancers. Specifically, HDGF is overexpressed in lung cancer and is a novel mitogenic growth factor for fibroblasts, vascular endothelial cells, and smooth muscle cells. High HDGF expression can also be found in keloid scar tissues but not in normal scar tissue. The molecular mechanisms of HDGF in cancer progression are poorly understood but we have demonstrated that lung cancer cells with down-regulated HDGF formed significantly smaller tumors in vivo (Zhang J., et al., “Down-regulation of hepatoma-derived growth factor inhibits anchorage-independent growth and invasion of non-small cell lung cancer cells,” Cancer Res 2006; 66:18-23). Diseases of the lung remain difficult to treat effectively. Therefore, a novel strategy to prevent and treat diseases due to abnormal proliferation of cells (i.e., fibroblasts, cancer cells) is needed. Ophthalmic conditions and diseases of the eye have a serious impact on life and livelihood of a great number of people. Ophthalmic conditions or pathologies include age-related macular degeneration, neovascular age-related macular degeneration, diabetic retinopathy, peripheral vitreoretinopathy, retinal vein occlusion (sometimes associated with neovascular glaucoma), and retinopathy of prematurity. Macular degeneration typically occurs in older people due to damage to the macula of the retina. The disease is divided into early, intermediate, and late types. Late macular degeneration also can occur in “wet” and, more commonly, “dry” form. This condition affects more than 190 million people. Current therapy for neovascular age-related macular generation (wet age-related macular degeneration) mainly relies on anti-VEGF-based therapy, includes ranibizumab (Lucentis™), a monoclonal antibody Fab fragment that binds VEGF, for intraocular use (a monthly intravitreal injection) and the older and less effective treatment of photodynamic therapy with verteporfin. Ranibizumab only stabilizes the condition and must be administered monthly by injection into the eye at high cost. An off-label alternative at lower cost is bevacizumab (Avastin™), which has not been subject to a randomized controlled clinical tria