An undisclosed company has picked up an integrin-targeting antibody from the University of California, San Francisco that could address the underlying pathology in chronic obstructive pulmonary disease by improving airway remodeling via suppressing transforming growth factor-b1.1 The home run will be whether the antibody reverses existing damage.

Although there is no shortage of marketed therapies and compounds in development for chronic obstructive pulmonary disease (COPD), the compounds mostly provide symptomatic relief by opening airways and suppressing inflammation.

None of the available therapies can reverse the underlying disease mechanism that results in progressive declines in lung function. Thus, patients remain in need of disease-modifying agents that can reverse or at least halt the emphysema caused by inflammatory triggers, viral infections and noxious agents such as cigarette smoke.2

About a decade ago, transforming growth factor-b1 (TGFB1) emerged as a key driver of the pathological airway remodeling that characterizes the disease. The cytokine sits in the extracellular matrix of lung mesenchymal cells in a latent form tethered to latency-associated peptide (LAP). COPD-inducing agents trigger an inflammatory response that increases integrin αvb8 levels, causing release of TGFB1 from LAP.

Stephen Nishimura, lead investigator of the UCSF group, found in previous studies that after TGFB1 is released from LAP, it activates signaling pathways and initiates airway remodeling in mice.3 However, TGFB1 is involved in many cellular processes, and systemic inhibition of the cytokine could create off-target toxicities. Thus, Nishimura and colleagues hypothesized that integrin avb8 might be a safer therapeutic target for COPD and investigated whether an antibody targeting the integrin b8 subunit of the dimer could disrupt the process.

Nishimura is an associate professor in the Department of Pathology at UCSF.

Homing in on integrin b8

The first step toward finding a site to attack on integrin b8 was to look at its conformation in the context of the natural integrin avb8 dimer. Using chromatography and electron microscopy, the team found that unlike other integrins, integrin b8 exists on the surface of cultured cells in a constitutively active form.

In that configuration, the integrin's extracellular portion is extended and can bind to LAP, triggering the release and activation of TGFB1.The extended domain also can reach into the extracellular matrix and adhere to Arg-Gly-Asp (RGD) motifs, which are specialized domains recognized by integrins and are common to many extracellular matrix proteins. The conformational studies suggested to Nishimura that an antibody targeting the single integrin subunit could disrupt TGFB1 activation while leaving the integrin's normal adhesion functions intact.

Using affinity maturation, the team optimized a mAb it previously made against integrin b8 (ref. 4) and tested it in a range of in vitro assays. The mAb binds an allosteric site on integrin b8, thus locking it in a conformation that shifts the affinity away from LAP and toward RGD substrates.

Next, the team looked at the efficacy of the mAb in a range of COPD-related models. In human fetal tracheal fibroblasts, the mAb suppressed expression of an almost identical spectrum of genes as a TGFB1 antibody. The integrin inhibitor blocked LAP binding with a Kd of 0.54 nM and prevented production of chemokine CC motif ligand 20 (CCL20; MIP3A), a COPD marker, in human lung fibroblasts.

Finally, the researchers established a mouse strain that exclusively expressed integrin b8 and used it to develop a model of cigarette smoke- and virus-induced COPD. Repeated doses of the integrin b8 mAb prevented disease-inducing airway obstruction and blocked activation of TGFB1 and inflammatory mediators.

The findings were published in Science Translational Medicine.

Corrective action

Having demonstrated that the integrin b8 mAb can prevent airway deterioration, the key question is whether it can improve established airway remodeling.

"Can [the integrin b8 antibody] induce or accelerate regression of established fibrosis, or does its potential mainly lie in preventing exacerbation?" asked Mark Lupher, former CSO of Promedior Inc.

Lupher now is president and cofounder of VeritasRx Consulting.

According to Lupher, the model used in the study is more physiologically relevant than a variety of cytokine overexpression models. "It will be important to further evaluate activity of the integrin b8 antibody in models of established lung fibrosis by delaying dosing until significant airway thickening and increased interstitial collagen have been demonstrated," he told SciBX.

David Griggs told SciBX that delivering the antibody directly to the lung could improve its therapeutic index.

"The antibody should be initially explored as an inhaled therapy alone or in parallel with a systemic therapy approach. The former presents a more formidable technical challenge for formulation and delivery but should enhance drug exposure to the accessible target tissue and limit potential for systemic side effects," he said.

Griggs is director of cellular and molecular biology at the Center for World Health & Medicine at Saint Louis University and adjunct assistant professor for pharmacology and physiology at the Saint Louis University School of Medicine. He also is a cofounder and scientific advisor at Antegrin Therapeutics LLC, which develops small molecule antagonists of profibrotic integrins.

Integrin effects

The fibrotic mechanisms at the root of COPD are similar to the ones that cause idiopathic pulmonary fibrosis (IPF), with aberrant TGFB1 activation by integrin complexes governing both processes. For example, integrin αvb6 has been highlighted as a key player in IPF.

Indeed, about a third of patients with IPF also exhibit COPD-specific airway remodeling.5 There even is a syndrome called combined pulmonary fibrosis and emphysema (CFPE), in which COPD and IPF coexist in the same patients.

According to Griggs, "This population may be particularly attractive for clinical evaluation using combined therapy of two or more specific integrin antagonists or using monotherapy with a single antagonist capable of simultaneous inhibition of integrin avb8 along with the other different TGFB1-activating integrins that predominate in lung."

Heather Arnett, a principal scientist at Amgen Inc. who is focused on fibrosis, said, "An important step toward differentiating the integrin b8 mAb may be to further understand the relative importance of integrin avb6 and integrin avb8, as well as other integrin combinations, in TGFB1 activation and lung fibrosis in patients."

"It would also be interesting to compare the integrin b8 mAb against integrin b6-targeting antibodies already in clinical development to treat fibrotic lung disease, which ostensibly target a similar mechanism of TGFB1 inhibition," said Lupher.

Biogen Idec Inc.'s anti-integrin avb6 mAb, STX-100, is in Phase II trials for IPF.

A patent covering the integrin b8 antibody and the COPD mouse model has been filed by the Regents of the University of California. The IP is licensed to an undisclosed industry partner that will conduct preclinical validation of the antibody before designing a Phase I trial in COPD.

Boettner, B. SciBX 7(29); doi:10.1038/scibx.2014.848
Published online July 31, 2014

REFERENCES

1.   Minagawa, S. et al. Sci. Transl. Med.; published online June 18, 2014; doi:10.1126/scitranslmed.3008074
Contact: Stephen L. Nishimura, University of California,
San Francisco, Calif.
e-mail: stephen.nishimura@ucsf.edu

2.   Wilkinson, T.M.A. et al. Am. J. Respir. Crit. Care Med. 173, 871-876 (2006)

3.   Kitamura, H. et al. J. Clin. Invest. 121, 2863-2875 (2011)

4.   Mu, D. et al. J. Cell Biol. 157, 493-507 (2002)

5.   Chilosi, M. et al. Respir. Res. 13, 3 (2012)

COMPANIES AND INSTITUTIONS MENTIONED

Amgen Inc. (NASDAQ:AMGN), Thousand Oaks, Calif.

Antegrin Therapeutics LLC, St. Louis, Mo.

Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass.

Center for World Health & Medicine at Saint Louis University, St. Louis, Mo.

Promedior Inc., Lexington, Mass.

Regents of the University of California, Oakland, Calif.

Saint Louis University School of Medicine, St. Louis, Mo.

University of California, San Francisco, Calif.

VeritasRx Consulting, Meridian, Idaho