Therapeutic+Applications

=**Therapeutic Applications**=

= = **[|Ablynx] is a Belgian based bio-pharmaceutical company that specializes in the discovery and development of nanobodies for therapeutic applications. The Nanobodies® produced by [|Ablynx] are patented both in Europe and the United States and they are developed specifically focusing on diseases in the following areas: cardiovascular, inflammation/infection/immunology, musculoskeletal, neurology and oncology. [|Ablynx] ’s Nanobodies® have similar properties to conventional nanobodies such as high target specificity and affinity as well as low inherent toxicity. The Nanobodies® produced are extremely stable, have the potential to be administered by means other than injection and can be easily manufactured. [|Ablynx] is currently partnered with Pfizer, Merck, Boehringer Ingelheim and Novartis in developing drugs for therapeutic applications. 1 Figure 8 shows the current development from Ablynx and their partners in lead, pre-clinical and phase trials for **Nanobodies®. 1 


 * Published Clinical Trial Results using Nanobodies **

Currently, there has been progress in the development of drugs that target cardiovascular disease, with much promise leading into phase testing. [|Ablynx] has patented and developed ALX-0081 and ALX-0681 to target Acute Coronary Syndrome and thrombotic thrombocytopenic purpura. These drugs are designed to target von Willebrand Factor, a blood protein to prevent the aggregation of platelets in the artery. 6 These drugs have passed preclinical and Phase I clinical trials and are currently proceeding through Phase II clinical trials. 1 **How ALX-0081 and ALX-0681 target vWF** Von Willebrand Factor (vWF) is a blood protein that mediates the aggregation of platelets (blood clots) by forming a bridge with a protein called Glycoprotein Ib (GpIb) at the A1 domain of vWF. 4  GPIb is found on the platelet membrane, and acts as a receptor for the vWF protein.
 * Cardiovascular Disease**

Studies have suggested that mutations in the A1 binding site on vWF changes the ability for vWF to properly maintain haemostasis. 18 Figure 10 specifically shows how the A1 domain of vWF and GpIb bind together, with the β-switch of GpIb aligning with the β-sheet of the A1 domain, resulting in the GpIb-A1 complex. 10 The representation of GpIb shows the blue N-terminus, labelled β-finger, and the leucine-repeats in green. The C-terminus is red, containing a loop called the β-switch and the disulfide bridges are yellow, whose purpose is to stabilize the folding of the molecule. 10 The primary targets for the binding of drugs are in the β-switch for GpIb and the most likely site requires the termini of the A1 domain to be dislodged. 10 These sites are the most likely binding sites because they were the specific areas that had mutations leading to the aggregation of platelets. 10 Since the binding site for vWF and GpIb is at the A1 domain of vWF, mutations and defects at this site can lead to unwanted thrombus (blood clots) and therefore, cause cardiovascular issues. 4,17



The cameloid anti-VWF A1-domain bivalent nanobody, ALX-0081, was developed by [|Ablynx] to bind to the A1 binding site of vWF to inhibit arterial platelet aggregation, and therefore prevent cardiovascular diseases. In preclinical trials, testing was conducted on primates, specifically on the femoral artery in baboons, to demonstrate that thrombus formation was in fact reduced. These results allowed [|Ablynx] to continue to progress in their drug development and move into Phase 1 studies. 11

In [|Ablynx] ’s Phase 1 study, 40 healthy male volunteers were given 0.5 mg to 12 mg doses of ALX-0081 via IV infusions for one hour. They experienced no adverse effects such as bleeding, and no immunogenic response was induced. However, no minor side effects such as nausea, or headaches were reported. Platelet aggregation was induced with ristocetin, an antibody that causes platelet clumping, as a biomarking method, and full inhibition was seen when volunteers were given 2 mg total dose over a period of 1 to 12 hour duration. From this testing, conclusions were made that the drug administered was highly potent, given that such a small dose was injected. 12 A subsequent placebo controlled study, phase 1b, was conducted to determine a safe drug dosage. ALX-0081 or placebo was given to 22 patients with stable cardiovascular conditions. ALX-0081 was administered along with standard anti-thrombotic drugs such as aspirin, clopidogrel, heparin, and Plavix®. The patients were given ALX-0081 or the placebo intravenously every 6 hours over a 24 hour time frame. The effectiveness of the drug in targeting vWF platelet aggregation was also measured using ristocetin induced platelet aggregation. Positive results were observed as all of the patients given ALX-0081 experienced platelet inhibition compared to the placebo group. With this success, [|Ablynx] proceeded with Phase II clinical trials for ALX-0081 in September 2009. 12 
 * ALX-0081 ALX-0681 Clinical Trials**

Another variation of ALX-0081 is ALX-0681. Its function is identical to ALX-0081 because it is also designed to target vWF to prevent platelet aggregation. However, it is administered subcutaneously rather than intravenously. 1 By having another administration method, a wider target audience can receive the benefits of the drug.

<span style="font-family: Arial,Helvetica,sans-serif;">Tumor necrosis factor, TNF, is a protein that induces an inflammatory response in an organism. However, it is also the source of many inflammatory and autoimmune diseases. These include rheumatoid arthritis and inflammatory bowel disease. However, the development of therapeutic treatments for these diseases are labour-intensive and thus very costly. Therefore, producing a nanobody specific for TNF can cut costs immensely, as well as put an effective and economic drug for patients.
 * Rheumatoid Arthritis**

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 13.2px; line-height: 19px;">**Preclinical Trials for anti-TNF Nanobody (anti-TNF Nanobody)** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 9.6px; line-height: 19px; vertical-align: super;">3 <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px; line-height: 19px;"> Rheumaoid arthritis is a disease that can be treated by targeting TNF. In Ablynx's preclinical studies, llamas were immunized with both human and mouse TNF. The anti-TNF nanobody proteins were collected and injected into mouse specimens with collagen induced arthritis. Researchers studied the monovalent (TR2, MT1) and multivalent (TR2-TR2, MT1-MT1) forms of human and mouse anti-TNF nanobodies respectively. They found that potency of bivalent forms were higher than monovalent form and prevented spreading of the diseases to unaffected joints. Also, an anti-serum albimun protein, AR1, was bound to the bivalent anti-TNF nanobodies. This was to increase specificity for the inflamed target tissues in the arthritic joint, where albumin is plentiful. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 19px;">



<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 14px;">**<span style="font-family: arial,helvetica,sans-serif; font-weight: normal; line-height: 19px;">[|Ablynx] ** is currently running Phase II Clinical Trials for the anti-TNF Nanobody drug with its partner, Pfizer and hopes to release anti-TNF nanobody to the market as early 2013.

In addition to ALX-0081, ALX-0681 and anti-TNF nanobody, <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 14px;">**<span style="font-family: arial,helvetica,sans-serif; font-weight: normal; line-height: 19px;">[|Ablynx] ** and its partners are currently developing Nanobody drugs to treat diseases such as cancer (ALX-0651 - targeting the CXCR4 protein), pulmonary (ALX-0171 targeting the respiratory syncytial virus), musculoskeletal (ALX-0141 targeting the RANKL molecule) and musculoskeletal diseases. The clinical trials for these drugs have yet to be released, but it is easy to see that Nanobodies look promising as economical, and effective treatments and/or cures for many diseases.
 * Other Nanobody Drugs**

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