The Bioamine System

Akari pipeline
Akari has a number of molecules derived from ticks that bind tightly and specifically (KD approximately 1nM) to bioamines including histamine and serotonin. The most advanced of these molecules, which binds histamine, has an established scalable GMP manufacturing process and has exhibited an excellent safety profile.

The bioamine binding molecules have a lipocalin-type protein fold which is related to that of Coversin, but have an amino acid identity of only 20-30% with Coversin. Akin to Coversin, they are stable, highly soluble, and do not appear to induce neutralizing antibody.

Role of bioamine system in inflammation and disease
Bioamines, including histamine (111Da) and serotonin (176Da), are small preformed mediators released by cells in response to a variety of signals. Both histamine and serotonin are neurotransmitters and play key roles within the brain and in the functioning of the gastrointestinal (GI) tract. Histamine regulates arousal and attention within the brain and stimulates hydrochloric acid secretion by the stomach. Serotonin regulates mood, sleep and appetite within the brain and gut peristalsis.

Beyond the central nervous system and gut, histamine was classically recognized to mediate the initial wheal, flare and itch seen in allergic immunoglobulin E (IgE) mast cell and basophil dependent reactions with these effects due to vasodilation, increased vascular permeability and sensory neural stimulation. More recently, histamine has been shown to have effects not only on inflammation but also on the elaboration of the immune response including regulation of cytokine release, granulocyte recruitment, and dendritic and T-cell maturation and differentiation.

Serotonin is produced predominantly by enterochromaffin like-cells of the GI tract. In the blood serotonin is actively taken up by platelets. At clot formation, platelets release serotonin which directly induces vasoconstriction and also regulates hemostasis. Serotonin is a growth factor for fibrocytes, and some agonists of serotonin have been shown to increase the risk of pulmonary hypertension. Histamine is well known to have a role in atopic dermatitis and may have roles in neuropathic pain and diabetic nephropathy.

Histamine and serotonin mediate their effects by binding to an array of G-protein coupled receptors, and two distinct gated ion channels, as well as via direct conjugation to proteins intracellularly.

Mode of action
The bioamine binding proteins are lipocalins which capture histamine and/or serotonin within the body of the protein. Both the histamine binding proteins and the serotonin binding proteins capture two molecules of bioamine within each molecule of protein. By doing so they can prevent interaction of the bioamines with all their GPCRs or disrupt direct conjugation to proteins intracellularly. Bioamine ligand capture is a unique mode of action and may allow the tick derived proteins to tackle diseases not amenable to the conventional anti-histamine and anti-serotonin drugs many of which are small molecules specifically targeting single G-protein coupled receptors or preventing serotonin reuptake.

Furthermore, unlike many of the small molecule anti-histamines, the bioamine binding proteins have been shown to not cross the blood brain barrier, therefore their action on histamine will be restricted to the body and not the central nervous system preventing any sedative effects.

The molecular architecture of the most advanced histamine binding protein has been characterized at atomic resolution allowing us to consider rationale design engineering of the molecule.