EULAR 2015: Anti-Inflammatory Drugs with Dual Targets

Advances in bioengineering are making it possible to develop therapies with molecules that can bind to more than one target.

Antibody-like molecules that can bind to more than one target—with the goal of having a more powerful effect than if those targets were treated separately in a combination of therapies—could become part of treatment regimens in rheumatic diseases over the next several years, an expert said here in a session at EULAR 2015, the annual congress of the European League Against Rheumatism (EULAR).

Advances in the bioengineering of these molecules, now most commonly seen in cancer treatment, have made development of potential therapies more feasible, with several companies now developing drugs that might be able to be applied in such diseases as pulmonary fibrosis, psoriatic arthritis and osteoarthritis, said Mark Throsby, PhD, chief scientific officer at Merus Biopharmaceuticals, based in The Netherlands.

“These are becoming easier to make in the therapeutic or drug-like setting,” Dr. Throsby said. “There are many companies now that have the tools to really bring these forward.”

In Development

Rather than aiming at one target and the biology surrounding that target, bispecific antibodies offer the possibility of combining two different targets and getting novel modes of action.

Merus’ Biclonics are bispecific, full-length human IgG antibodies developed for use in cancer immunotherapy. Bispecifics have been developed to block two checkpoint inhibitors at once; to block one checkpoint inhibitor and provide a co-stimulatory signal, in a “release the brakes and push on the accelerator” approach; and to target an overexpressed signaling receptor and an immunomodulatory pathway, Dr. Throsby said.

AbbVie and Sanofi are in Phase 2 clinical trials with several bispecific antibodies—for example, one that blocks TNF and IL-17, another that blocks IL-1 alpha and IL-1 beta, and one that blocks IL-4 and IL-13. Dr. Throsby said it will be interesting to see how the body reacts to these therapies, because they are different from naturally occurring IgG antibodies.

“I think one of the key things to look for would be immunogenicity, because this is not looking exactly like an IgG, and immunogenicity is very difficult to tease out in preclinical studies,” Dr. Throsby said.

Macrogenics and Takeda have teamed up on the development of a bispecific antibody targeting CD32B and CD79B for a B cell-targeted therapy that doesn’t lead to B cell depletion. This is being studied for potential use in RA and systemic lupus erythematosus, and is also in Phase 2.

Dr. Throsby said the main focus—neutralization of two cytokines at once—has a challenge: differentiating themselves from just using two different monoclonal antibodies in combination.

“The main driver there may be cost and convenience,” he said. “But there are much more opportunities to be explored in this field.”

Efficacy

A separate talk addressed another bispecific antibody, COVA322, which is being developed by Switzerland-based Covagen. It binds simultaneously to TNF and IL‑17A. COVA322 is made by fusing two fynomers, small binding proteins, to an anti-TNF antibody, said Mathias Locher, PhD, Covagen’s chief development officer.

The developers are encouraged by studies showing, in a collagen-induced arthritis mouse model, that a combination of anti-TNF and anti-IL17 treatment has been shown to produce better efficacy and long-lasting remission, compared with either TNF or IL-17 blockade alone.¹

Both of COVA322’s fynomers bind to IL-17A—and one of them also binds to TNF. Dr. Locher said the avidity gain strengthens the connection to IL-17A homodimer, while other IL-17 family members are not neutralized.

In pre-clinical studies in mice and monkeys, the drug showed no adverse cardiovascular, respiratory or central nervous system effects. The immunogenicity profile was similar to that of adalimumab.

It is now being studied in a psoriasis trial of 39 patients to evaluate safety and biological activity.

The developers say it is designed for superior efficacy compared with existing treatments in inflammatory disease, most of which produce similar responses.

“There is a huge area of opportunity to increase the activity of new treatments,” Dr. Locher said.

Inflammatory Mediator Inhibitor

Another drug—presented by Erik Hack, MD, PhD, head of the infection and immunity research program at University Medical Center at Utrecht—targets both IL-4 and IL-10. In vitro, the “synerkine,” as researchers are calling it, has been found to be a potent inhibitor of the release of inflammatory mediators by cells. It also inhibits spontaneous release of inflammatory mediators by the joint tissue of RA and osteoarthritis patients and has been seen to have a cartilage-protecting effect. In a mouse model, it has been found to reverse pain sensitivity.

These traits make the drug particularly attractive as a potential osteoarthritis treatment, Dr. Hack said. According to unpublished data that he presented, the drug seems to reduce pain in a canine model of the disease.

“We think,” he said, “that this molecule has potential as an anti-inflammatory and analgesic therapy.”

Thomas R. Collins is a freelance medical writer based in Florida.

Reference

1. Alzabin S, Abraham SM, Taher TE, et al. Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway. Ann Rheum Dis. 2012 Oct;71(10):1741–1748.