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R&D Focus

Collabody™ Acts as New Protein Drug

Video of Collabody.

ITRI developed Collabody™, a recombinant protein engineering platform for making multi-trimeric protein binders. It utilizes a short triplex-forming collagen-like peptide (about 40 amino acids in length) as a scaffold protein binder for fusing with antibody fragments, hormones, cytokines, lymphokines, growth factors, lectins, enzymes, soluble receptor fragments and chemo agents. The autoimmune system in our body is vital for protection against invading viruses and bacteria germs. Anti-CD3 Collabody™ acts as a protein drug for immune disease treatment.

Collabody acts as a protein drug for immune disease treatment because of its better drug potency and lower side effects.

Collabody acts as a protein drug for immune disease treatment because of its better drug potency and lower side effects.

Due to the multi-trimeric nature of Collabody™, Collabody™-derived protein molecules can greatly reduce the dissociation rate of their target molecules and exert more functional potency than the traditional mono- or bi-valent counterparts. Moreover, upon binding, Collabody™ molecules can trigger clustering (or crosslinking) of their cognate target molecules on the cell membrane. Depending on the characters of different target-binding partners, the clustering effects can lead to target internalization, cell activation, or apoptosis.

Collabody™ is advantageous because it can be mass produced and purified in the same way as IgG molecules. Treatment with low dosage has sufficient efficacy in mouse models, including NOD/ShiLt J mice for type 1 diabetes, experimental autoimmune encephalomyelitis mice for multiple sclerosis, and NZB/W F1 mice for systemic lupus erythematosus. It does not cause cytokine storm side effects and is safety approved in mouse pre-clinical tests.

The murine anti-CD3 monoclonal antibody OKT3 (Orthoclone OKT3®; Ortho Pharmaceutical Corp., Raritan, NJ) has been shown to be an effective immunosuppressive and immunomodulatory agent for the treatment of acute allograft rejection and autoimmune diseases. However, the administration of OKT3 in humans is complicated by T-cell activation, resulting in life threatening cytokine release syndrome. Efforts have been made to develop non-mitogenic forms by altering binding to Fc receptors (mainly FcRI) or by IgG isotype switching to decrease the FcRI binding affinity. The structure design of its first derivative, anti-CD3 Collabody™ (coltelizumab), is meant to resolve the narrow therapeutic window of the existing anti-human CD3 antibody products – teplizumab and otelixizumab, both of which failed in clinical phase 3 trails in treating patients with type 1 diabetes mellitus disease. The trivalent F(ab’)3 structure of coltelizumab has been proven to enhance the T-cell receptor modulation activity (drug potency) more than the bivalent teplizumab antibody counterpart. Unlike the Fc-engineered existing anti-CD3 antibodies which can still activate T cells, resulting in mild cytokine release syndrome, coltelizumab does not contain the Fc fragment and so does not cause any Fc-receptor binding activity. Therefore, coltelizumab is a genuine non-mitogenic version of anti-CD3 antibody and can be used to treat acute allograft rejection and autoimmune diseases with greater drug potency and lower side effects than the current low-mitogenic versions in clinical trials. ITRI finds that anti-CD3 Collabody™ coltelizumab can greatly increase the therapeutic window for treating acute allograft rejection and autoimmune diseases.