Aptevo Therapeutics Inc. (APVO)

[Titan V]

Special Report on Immunology & Autoimmunity: Turn of the coin
http://ddn-news.com/index.php?pg=77&articleid=13140

...Aptevo Therapeutics is taking a similar approach to Cue’s with its ADAPTIR platform, where the co-stimulatory component is the cytokine IL-10.

As Jane Gross explains, cytokines are pleiotropic in that they can both up- and down-regulate various activities in the immune system, making them both attractive but potentially risky targets.

“What people have started to realize in the last four or five years is that you can create a bispecific that targets the cytokine in a special way,” she says.

“Some have attached cytokines to antibodies,” she reports. “Other people have PEGylated them in a particular way, so they target a specific set of receptors and they increase the half-life.”

“We prefer the strategy of recombinantly fusing a cytokine to a structure that has the antibody-like modality,” she notes. “The antibody again gives you the increased half-life, the ability to manufacture in a particular way, and the targeting arm targets it to a specific cell type, or you could target to a specific receptor.”

This approach is the basis of the company’s autoimmune lead APVO210.

“With APVO210, what that drug has allowed us to do is target IL-10 to a particular set of cell types, which are more appropriate for down-regulating the immune system,” Gross explains.

”APVO210 targets the myeloid and dendritic cell lineages, and not lymphocytes,” she continues. “The myeloid and dendritic cell lineages are the relevant population to shut down the pathogenesis of the disease.

“The lymphocytes are the ones that would rev up the immune system, so by eliminating that, it is beneficial for autoimmune disease.”

Another part of that equation is a specific type of regulatory T cells known as Tr1, which are dedicated to maintaining immune tolerance.

As a first step, Stanford University’s Maria Grazia Roncarolo and colleagues demonstrated last year that APVO210 was able to differentiate CD14+ monocytes in vitro into tolerogenic dendritic cells. These dendritic cells were able to induce Tr1 cells, which inhibited primary T cell proliferation.

“The specific ability of APVO210 to deliver IL-10 to CD86+ cells, as compared to IL-10 [alone], which has a pleiotropic effect, may have significant advantages for in vivo use,” the authors wrote. “The systemic administration of IL-10 in vivo has indeed been limited by the development of adverse effects that are due to its stimulatory functions on CD8+ T cells and B cells.”

They further added, “We hypothesize that the in vivo use of this molecule could decrease the risk of triggering specific T- and B-cell responses associated with IL-10 systemic delivery, and, therefore, lead to more targeted and safe control of undesired inflammatory and autoimmune responses.”