Integrin Biology

Overview

Integrins are a widespread, diverse family of proteins at the heart of many cellular biological processes. They are also believed to play a role in a variety of serious chronic diseases, including autoimmune, cardiovascular and metabolic diseases, as well as fibrosis and cancer.

An integrin’s activity is related to its particular shape or conformation. Morphic’s unique understanding of integrin biology drives its efforts to stabilize specific conformations and thereby activate or inhibit specific integrins to appropriately modify disease.

The details

As adhesion receptors, integrins mediate many key cell-cell and cell-extracellular matrix interactions. They are heterodimers (a union of two different proteins) composed of an α subunit and a β subunit. Humans have 18 different types of α subunit and 8 different β subunits. Through combination these result in the 24 known human integrins, all potential targets of Morphic’s platform.

Integrins are the only human receptors known to signal bi-directionally, both “inside>out” and “outside>in”, to integrate intracellular and extracellular information. This bi-directional signaling ability allows integrins to affect virtually every aspect of cell and organ homeostasis and may partly explain the diversity of the processes with which they are involved.

Disease focus areas

The therapeutic potential of integrins has long been widely recognized because of their central roles in almost all phases of human biology as well as many diseases. Morphic is focused on using its integrin discovery platform to discover and develop first-in-class oral small molecule integrin therapeutics across a range of disease areas with an initial focus on autoimmune diseases, fibrosis as well as cancer.

Autoimmune Diseases

The aberrant activation of the immune system against the body leads to local or systemic autoimmunity. The incidence of autoimmune disease is increasing in the industrialized world, including conditions such as ulcerative colitis, Crohn’s disease, psoriasis and systemic lupus erythematosus.

The infiltration of immune cells into inflamed tissues is central to any inflammatory response including autoimmunity. Integrins belonging to the α4 and β2 subfamilies control the interactions that allow immune cells to migrate from the general circulation to reach sites of inflammation. In addition, integrins facilitate the retention of immune cells at sites of chronic inflammation by binding to components of the extracellular matrix. Blocking these integrins may therefore repress pathological autoimmunity across many conditions.

Morphic’s lead wholly-owned development program is a small molecule oral inhibitor of α4β7 that is in preclinical development for Inflammatory Bowel Disease, or IBD.

Fibrosis

Sustained organ injury leads to uncontrolled fibrosis, a pathological process characterized by the formation of excessive extracellular matrix. Fibrosis is a common feature of most chronic diseases involving tissue injury and affects multiple organs, such as the lungs, liver, skin, and kidney. The replacement of normally functional cells with scar tissue greatly contributes to a progressive loss of organ function and eventually leads to organ failure.

The pro-fibrotic cytokine TGF-β is a key regulator of fibrosis, but attempts to globally suppress its activity have suffered from a narrow therapeutic index (dose-limiting toxicity). Several integrins of the RGD-binding group play a dominant role in local activation of TGF-β in diseased tissues. Inhibition of these integrins is therefore a compelling strategy for treating chronic fibrotic diseases with significant advantage over global TGF-β inhibitors.

Our most advanced development candidate, MORF-720, is in preclinical development for idiopathic pulmonary fibrosis, or IPF, together with our partner AbbVie. MORF-720 is a small molecule inhibitor of the integrin αvβ6.

Cancer

Cancer is the leading cause of death in the Western world. Recent advances in immuno-oncology are changing the standard of care of many types of cancers but only a fraction of patients respond to the new immunotherapies, representing huge opportunities for therapeutic improvement.

TGF-β is a key target for cancer treatment because excessive local TGF-β levels promote an immunosuppressive tumor microenvironment leading to poorer patient outcomes. This TGF-β pathway impacts both immune and non-immune cell types to support tumor growth and greatly reduce the potential of anti-tumor immune responses. Therefore, selective inhibition of TGF-β-activating integrins offers a significant opportunity to reduce tumor immune tolerance and be a powerful therapeutic approach in immuno-oncology.

Morphic has early-stage integrin inhibitor programs targeting TGF-β for various indications in oncology.