F-652
Introduction
F-652, under development, is intended to treat inflammatory diseases with tissue injuries and immunologic disorders including graft vs host disease (GvHD), acute alcoholic hepatitis, and acute pancreatitis. F-652 is a recombinant fusion protein consisting of human interleukin 22 (IL-22) and human IgG2-Fc and is manufactured in Chinese Hamster Ovary (CHO) cells. It contains two IL-22 molecules at the N-terminal of Fc fragments (an IL-22 dimer). F-652 is a first-in-class biologic therapy with a novel mechanism of action to treat acute inflammatory diseases as well as immunologic disorders. F-652 has an immunoglobulin-like structure.

IL-22 is produced by CD4 T-cell subsets, Th17/Th22 cells, NK cells and LTi-like cells. Serum IL-22 levels are up-regulated during inflammation in human diseases. IL-22 plays an important role in controlling bacterial infection, homeostasis, and tissue repair by binding a cell surface IL-22 receptor and forms a complex which subsequently activates the STAT3 signaling pathways. The IL-22 receptor complex consists of IL-22 R1 and R2. The IL-22 R2 or IL-10 R2 are ubiquitously expressed. The specific IL-22 R1 which is restrictedly expressed on epithelial cells such as keratinocytes, bronchial and intestinal epithelial cells and hepatocytes. The IL-22 R1 is not expressed in hematopoietic/immune cells.

F-652 to treat inflammatory diseases
IL-22 had been considered a pro-inflammatory cytokine for some time based on the induction of acute response proteins in the liver and activation of keratinocytes in the skin of mice. IL-22 acts on epithelial cells of various organs including gastric, intestinal and lung epithelial cells, hepatocytes, pancreas acinar cells by STAT3 signaling pathways. We believe that IL-22 plays key roles in the tissue protection and repair during injuries induced by inflammation/immune responses. We have not identified any evidence of a direct pro-inflammatory role of IL-22 in human studies.

Inflammation is a very complex biological response of tissues to harmful stimuli, or inflammatory triggers, such as pathogens/infections, tissue injury, tissue stress or malfunction. Inflammation is also a protective response involving immune cells, blood vessels, and molecular mediators. The physiological purpose of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory response, and to initiate tissue repair. The contrast and duality of tissue injury/damage and tissue repair of inflammation can be best illustrated in the traditional philosophy of “Yin & Yang”.

Current approaches of new drug discovery for inflammatory diseases are mainly focused on the anti-inflammatory side of inflammation, either by immune-suppression, or by blocking inflammatory mediators. We believe that F-652 (IL-22) provides the cells with a “do not die and recover” signal during inflammatory responses. Thus, F-652 provides a novel mechanism of action to combat inflammatory diseases with unmet medical need.

 


         F-652: Mechanism of Action            Structure of F-652

F-652 clinical development status
Generon is the first company to conduct clinical trials with rhIL-22 to treat human diseases. Two Phase I studies have been completed in healthy subjects in both Australia and China. Generon is developing three acute indications for F-652 to treat GvHD, alcoholic hepatitis, and acute pancreatitis. The status of clinical development for F-652 is shown in table below.

 

Study

Subject

Objective

Regulatory

Status

Ph I

Healthy men

Safety, PK

Australia

Completed

Ph I

Healthy men

Safety, PK

CFDA

Completed 

Ph Ib

Acute pancreatitis

Safety & Efficacy

CFDA

Planning

Ph IIa

Alcoholic hepatitis

Safety & Efficacy

FDA

Ongoing

Ph IIa

GvHD

Safety & Efficacy

FDA

Ongoing



Reference
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