Fibroblast activation protein (FAP) targeted imaging and therapy in fibrosis

A fibroblast and activated protein technology, applied in the field of fibroblast activated protein (FAP) targeted imaging and fibrosis treatment, can solve difficult problems

Pending Publication Date: 2021-06-04
PURDUE RES FOUND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In more advanced cases, lung transplantation may be the last option, but finding an HLA match is often difficult and avoiding transplant rejection can be challenging

Method used

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  • Fibroblast activation protein (FAP) targeted imaging and therapy in fibrosis
  • Fibroblast activation protein (FAP) targeted imaging and therapy in fibrosis
  • Fibroblast activation protein (FAP) targeted imaging and therapy in fibrosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1. Design and synthesis of FAPL-FITC conjugates for analysis of FAP targeting

[0184] In this example, according to figure 1 The protocol shown in produces an imaging agent conjugate comprising a FAP targeting ligand (FAPL) and a fluorescein (eg FITC).

[0185] To determine the in vitro binding characteristics of the conjugate such as binding affinity to FAP and its biodistribution in FAP-expressing cells, the FAPL-FITC conjugate was incubated with the FAP-transfected cell line HLF1 (human fibroblasts) , using confocal microscopy and flow cytometry to visualize the specific targeting of the conjugate to a FAP-expressing cell line, and its subsequent endocytosis in this cell line. see figure 2 and its legend, which shows that FAPL-FITC binds well with good competition in the hFAP-HLF1 cell line. In addition, FAP ligands can recognize and target FAP with good specificity. The FAPL_FITC conjugate is internalized after receptor engagement. This suggests tha...

Embodiment 2

[0186] Example 2. Binding of human IPF patient cell lines to FAPL-FITC

[0187] In this example, human IPF patient cell lines and non-IPF control cell lines were stained with FAP antibody and [alpha]SMA antibody, respectively. Confocal microscopy showed that both FAP and αSMA were predominantly expressed in IPF lung fibroblasts. see image 3 a. When IPF patient cell lines were incubated with FAPL_FITC, flow cytometry analysis showed image 3 FAPL_FITC stained samples in B.

Embodiment 3

[0188] Example 3. Design and synthesis of PI3KI1 and FAP-PI3KI1

[0189] In this example, we provide a novel pan-PI-3 kinase-mTOR inhibitor named PI3KI1. This potential IPF drug has a good handle to incorporate a releasable linker for conjugation with a targeting ligand such as the FAP ligand in Examples 2-3.

[0190] Design and synthesis of new pan-PI-3 kinase-mTOR inhibitors as Figure 4 shown in .

[0191] The synthetic scheme of a new FAP-targeting pan-Pi3K inhibitor (FAPL_PI3KI1) is as follows: Figure 5 shown in .

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Abstract

Excessive deposition of extracellular matrix is a hallmark of Idiopathic pulmonary fibrosis (IPF), it is advantageous to target the cells and the mechanisms associated with this process. By targeting myofibroblasts (specialized contractile fibroblasts) that are key for the development of IPF with drugs conjugated with fibroblast activation protein (FAP), this technology helps minimize the production of extracellular matrix in the lungs and provides a new treatment option for patients diagnosed with IPF.

Description

technical field [0001] The present disclosure provides conjugates and methods of using the same to image and / or treat idiopathic pulmonary fibrosis (IPF). Specifically, fibroblast active protein (FAP)-targeted imaging agents or therapeutic drugs are delivered to IPF to guide the diagnosis of IPF or significantly reduce the pathological extracellular matrix deposition of IPF. Background technique [0002] Fibrotic diseases are major health problems affecting large numbers of individuals worldwide. [0003] Under pathological conditions, normal tissue repair responses escape homeostatic regulatory mechanisms and evolve into an uncontrolled fibrotic process characterized by progressive overproduction of extracellular matrix, which disrupts normal organ architecture and ultimately leads to organ failure. [0004] Virtually every organ in the human body is affected by physiological and pathological fibrotic responses, but the most commonly affected organs are the lungs, kidneys...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/574A61K49/00A61K51/04G01N33/58
CPCG01N2800/12G01N33/532G01N2333/96411G01N33/582G01N33/60G01N2800/7052G01N33/6893C07D401/14A61P11/00C07D405/14A61K51/0455A61K51/0497A61K49/0032A61K49/0043A61K49/0052A61K47/545C07B59/004C09B57/00A61K31/4709A61K51/0482
Inventor 菲利普·S·洛苏拉杰·U·黑蒂亚拉奇李彦兴乔蒂·罗伊
Owner PURDUE RES FOUND INC
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