DUBLIN – Argenx NV is getting $40 million up front plus up to $645 million in milestones in an immuno-oncology pact with Abbvie Inc., based around its first-in-class, preclinical antibody, ARGX-115, which inhibits Garp (glycoprotein A repetitions predominant), a novel target involved in maintaining the immunosuppressive activity of regulatory T-cells (Treg cells).

It's the biggest deal to date for Breda, the Netherlands-based Argenx, and it validates an initiative within the company to enter academic collaborations based on novel, disease-causing targets. "This will be the way we build our pipeline going forward," Argenx's senior vice president of business development, Debbie Allen, told BioWorld Today.

Abbvie, of North Chicago, came out on top in a competitive bidding process triggered by broad industry interest in the program.

"They wouldn't be the first company to come to mind in immuno-oncology," Allen said. "Their pipeline is extremely interesting and, with the acquisition of Pharmacyclics, has become even more so," she added.

In addition to the financial package on offer, Argenx gains co-promotion rights to ARGX-115 in Europe, as well as the right to combine the antibody with other molecules in its pipeline. It will also receive tiered royalties on product sales. Moreover, Abbvie and Argenx will enter a research collaboration to explore Garp biology further. "Both companies believe there is more value in this target, beyond ARGX-115 alone." Allen said.

Abbvie has the right to license whatever additional programs may emerge from that effort.

Included in the deal are two near-term preclinical milestones, each worth $10 million. Argenx will continue its ongoing preclinical development of ARGX-115. Once it completes an investigational new drug application package, Abbvie will be able to trigger its licensing option and take the program forward.

Argenx had initially developed preclinical data in what Allen described as "a surrogate model," in graft-vs.-host disease. "Those data were compelling enough to attract the attention we saw," she said. It has since worked in several tumor models – and has also explored potential off-target effects associated with Garp expression in other cells. "To date we have seen no cross-reactivity that would raise a tox concern in hepatic stellate cells or platelets," she said.

Garp inhibition offers an alternative to Treg cell depletion, which has proved difficult to achieve due to the lack of cell surface markers that are specific to that lineage. Argenx gained exclusive rights to the Garp program from the de Duve Institute, at the Catholic University of Louvain, in Belgium, in early 2015. The associated intellectual property is based on the work of Sophie Lucas at the institute, whose lab has established that Garp plays a key role in the activation by Tregs of the immunosuppressive cytokine transforming growth factor beta 1 (TGF-beta1).

An inactive homodimeric form of TGF-beta1 is cleaved by furin to give rise to a latent complex, comprising a C-terminal mature TGF-beta1 molecule linked to an N-terminal fragment, latency-associated peptide. Further activation is required for the release of TGF-beta1 from the complex. Lucas and colleagues have shown that Garp – a protein whose gene was cloned in the early 1990s – is necessary but not sufficient for TGF-beta1 activation by Treg cells. ARGX-115-mediated Garp inhibition disrupted Treg-mediated immunosuppression in a mouse model – the data appeared in the April 22, 2015, issue of Science Translational Medicine.

The activation process is specific to Treg cells, so inhibiting Garp does not interfere with the activation of TGF-beta1 by other cell types. The specificity of the approach bypasses the safety issues associated with systemic TGF-beta inhibition, which can give rise to basal cell carcinoma and other skin lesions.

The deal with Abbvie will boost Argenx's international profile in terms of both antibody development and cancer biology. Its Simple antibody platform comprises the variable regions of the conventional antibody repertoire found in camelids, such as llamas and camels, fused to human Fc domains. Argenx can easily generate in vivo a highly diverse panel of antibodies against a given target, boosting its hit rate against difficult targets. Its earlier deals, with Dublin-based Shire plc and Ballerup, Denmark-based Leo Pharma A/S are smaller scale and based, respectively, on rare diseases and inflammatory skin conditions. (See BioWorld Today, June 6, 2014, and May 22, 2015.)

Its pipeline contains three clinical-stage programs. ARGX-110 targets CD70 and is in a phase Ib trial in blood cancers and solid tumors. ARGX-111, which targets the receptor tyrosine kinase c-Met (mesenchymal-epithelial transition factor), is also in phase Ib in solid tumors and hematological cancers. Phase I safety data on ARGX-113, which targets the neonatal receptor FcRn and is in development for the autoimmune condition myasthenia gravis, are due around midyear.

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