Otelixizumab, also known as TRX4, is a

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ...

, which is being developed for the treatment of type 1 diabetes and other autoimmune diseases. The antibody is being developed by Tolerx, Inc. in collaboration with GlaxoSmithKline and is being manufactured by Abbott Laboratories.

Mechanism of action

Otelixizumab is one of several investigational monoclonal antibodies that target CD3, a T lymphocyte receptor involved in normal cell signaling. More specifically, otelixizumab targets the epsilon chain of CD3. Data suggest that the drug works by blocking the function of effector T cells, which mistakenly attack and destroy insulin-producing

beta cells Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dim ...

, while stimulating regulatory T cells, which are understood to protect against effector T cell damage, thus preserving the beta cells' normal ability to make insulin. Proof of concept was established in a randomized, placebo-controlled Phase 2 study. These data demonstrated otelixizumab’s ability to preserve beta cell function, as measured by

C-peptide The connecting peptide, or C-peptide, is a short 31-amino-acid polypeptide that connects insulin's A-chain to its B-chain in the proinsulin molecule. In the context of diabetes or hypoglycemia, a measurement of C-peptide blood serum levels can ...

, in patients up to 18 months after dosing, as well as reduce the need for delivered insulin to maintain glucose control.

Clinical progress

The efficacy and safety of otelixizumab for the treatment of autoimmune type 1 diabetes was studied in a pivotal Phase 3 study called DEFEND (Durable-response therapy Evaluation For Early or New-onset type 1 Diabetes). DEFEND was a randomized, placebo-controlled Phase 3 trial designed to enroll approximately 240 adult patients, age 18 to 45, with newly diagnosed autoimmune type 1 diabetes. DEFEND was conducted at multiple centers in North America and Europe. The trial was designed to evaluate whether a single course of otelixizumab, administered not more than 90 days after the initial diagnosis, would reduce the amount of administered insulin required to control blood glucose levels by inhibiting the destruction of beta cells. The trial failed to show efficacy of the treatment.

Orphan drug status

Otelixizumab has been granted " orphan drug" status by the

U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

Chemistry

As a monoclonal antibody, otelixizumab consists of two heavy chains and two light chains. The heavy chains are

humanized Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal an ...

γ1 (gamma-1) chains from rats, making otelixizumab an immunoglobulin G1. The light chains are chimeric human/rat λ (lambda) chains.

References

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