Multimeric Biotherapeutics, Inc.

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About CD40 Ligand (CD40L)

CD40 ligand (CD40L) is one of the most important molecules ever discovered by medical science. It is the prime mover in establishing cellular immunity against cancer and virus infections. This protein is part of an evolutionarily ancient family of tulip-shaped proteins called the TNF SuperFamily (TNFSF) in which each member is formed as a trimer of three protein chains. The scientific literature contains over 12,000 papers that reference CD40L and the CD40 receptor, and their functions are carefully described in all modern textbooks on immunology.

A first-generation version of CD40L (sCD40LT or Avrend®) was developed to treat cancer. Even without knowing how to use this protein, an initial Phase I study in 2001 found that 38% of cancer patients responded to treatment and one patient with metastatic cancer was completely cured. This study used a dose of ~10 mg given systemically but caused enough toxicity to end further studies. However, academic investigators later showed that a smaller ~1 mg dose could be used safely in children and stimulated immunity in patients with a congenital absence of CD40L. This study demonstrated that CD40L can be used to stimulate strong immune responses in humans, a property that makes this molecule an ideal booster or “adjuvant” for long sought-after vaccines. Yet until now, no company has taken on the task of developing a next-generation formulation of CD40L for human use.

A further technical roadblock was a misunderstanding of how CD40L actually works. Rather than simply binding to the CD40 receptor, many trimers of CD40L are needed to pull CD40 receptors together into a patch within the membrane of responding cells. This patch of clustered CD40 receptors sets off a chain of events that carries out the CD40L stimulus. This new understanding allowed two scientists, Dr. Richard Kornbluth (Scientific Founder of Multimeric) and Dr. Jürg Tschopp (Professor of Biochemistry at the University of Lausanne) to invent exactly the same technology: a way to make many-trimer forms of CD40L and other TNFSF ligands by joining them to a naturally multimerizing scaffold protein. For example, Multimeric’s lead molecule, MegaCD40L™, has two CD40L trimers held together by joining them with Acrp30, a natural serum protein (see Technology). Numerous academic laboratories all over the world have confirmed that MegaCD40L™ is a strong activator of human and mouse immune cells and is a powerful adjuvant for much needed vaccines (see Publications).