Beyond Achondroplasia

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B-701 – New potential treatment for achondroplasia

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The motto of BioClin Therapeutics is “Developing protein therapeutics for high unmet medical needs”. And this has a deep meaning for achondroplasia.

BioClin is a privately held biotechnology company funded in 2010, in California. Their leading product is B-701, that is an anti-FGFR3 mAB (monoclonal antibody), developed for the treatment for metastatic bladder cancer and achondroplasia. BioClin is the first company to study the potential application of a mAB for achondroplasia. So far, many studies have been published related to antibodies FGFR3 and cancer. I have found papers related to FGFR3 and cancer, dating back to 2005:

2005 – Targeting the extracellular domain of fibroblast growth factor receptor 3 with human single-chain Fv antibodies inhibits bladder carcinoma cell line proliferation, Martínez-Torrecuadrada J et al.,Clin Cancer Res. 2005 Sep 1;11(17):6280-90
2006. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Trudel S,et al., Blood 2006 May 15;107(10):4039-46.
2009. FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma, Hadari Y, Schlessinger J. J Clin Invest. 2009 May;119(5):1077-9.

And recently, at the ISDS meeting Prof. Savarirayan showed during his lecture one slide about the antibody blockade approach for achondroplasia. After this, I found the following article:

2015. Redesigning a Monospecific Anti-FGFR3 Antibody to Add Selectivity for FGFR2 and Expand Anti-tumor Activity, Carter PJ et al, Mol Cancer Ther. 2015 Aug 12. pii: molcanther.1050.2014.

Abstract: “Fibroblast growth factor receptors (FGFR´s) are attractive candidate targets for cancer therapy because they are dysregulated in several human malignancies. FGFR2 and FGFR3 can be inhibited potentially without disrupting adult-tissue homeostasis. By contrast, blocking the closely related FGFR1 and FGFR4, which regulate specific metabolic functions, carries a greater safety risk. An anti-FGFR3 antibody was redesigned here to create function-blocking antibodies that bind with dual specificity to FGFR3 and FGFR2 but spare FGFR1 and FGFR4. R3Mab, a previously developed monospecific anti-FGFR3 antibody, was modified via structure-guided phage display, and acquired additional binding to FGFR2. The resulting dual-specific antibodies blocked FGF binding to FGFR3 and FGFR2 and inhibited downstream signaling… A monospecific antibody can be exquisitely tailored to confer or remove binding to closely related targets in order to expand and refine therapeutic potential

What is a monoclonal antibody?

An antibody is a protein naturally produced by our body that binds to other proteins (usually from pathogens), called a antigens, on specific amino acid sequences. Our body produces many antibodies specific for different antigens, which circulate throughout the body until they find and attach to their antigen. Once attached, their natural function will be to recruit other parts of the immune system to destroy the cells which show the antigen on their surface. Researchers can design antibodies that specifically target a certain antigen, such as one found on cancer cells to either destroy those cells using the immune system or another molecule that’s toxic for those cells (targeting only them, this way) or, in other cases, bind to certain receptors in cells, activating them or inhibiting them. They can then make many copies of that antibody in the lab from the same source cells. These are known as monoclonal antibodies (mAbs), and they have many uses in research, treatment and diagnosis.

production_illust

Hybridomes have the characteristics of the two different types of cells, and are able to both produce antibodies and reproduce infinitely. Credits: http://www.kyowa-kirin.co.jp/antibody/english/ about_antibody/production.html

Monoclonal antibodies are the basis of a third of all biotech products in clinical development. For their discovery Milstein and Köhler won the 1984 Nobel Prize in Physiology or Medicine.

What is connection between mutant FGFR3 in achondroplasia and antibodies?

FGFR3 mutation causes a gain-of-function of this protein in a variety of cancers, as in achondroplasia, where this mutation increases the receptor signaling and enhances negative regulation of growth plate chondrocyte proliferation (stalling their development).

Most, if not all, potential solutions to treat achondroplasia until now have been directed to attack the mutant FGFR3 in chondrocytes.

Until now, the biggest obstacles in finding a molecule to block FGFR3 in achondroplasia have been:

  1. Molecule size
  2. Specificity
  3. Toxicity

But antibodies are typically large proteins, with an approximate size of 150kDa and only very small molecules reach the growth plate, under 50Kda. I couldn’t find B-701 size description.

Intact_antibodies_and_a_variety_of_antibody_fragments

Antibodies and some artificial molecules derived from antibodies. Credits:https://commons.wikimedia.org/wiki/File:Intact_antibodies_and_a_variety_of_antibody_fragments.png

For specificity, B-701 is described has highly specific for the FGFR3 receptor and does not cross-react with the other fibroblast growth factor receptors (FGFR1 and FGFR4). It is being used to inhibit signaling through this pathway in bladder cancers that express wild-type or mutated FGFR3 and has potential for application in achondroplasia.

Toxicity is being assessed through animal testing. During preclinical phase the pharmacodynamics (what the drug does to the body) (PD) and pharmacokinetics (what the body does to the drug) (PK) of the drug are also assessed.

For BioClin, “the single point activating mutation in the FGFR3 protein in achondroplasia may be an elegant and rational target for B-701, given its precise targeting of FGFR3″.

Pipeline

B-701 is in preclinical testing for achondroplasia for which FGFR3 antagonism may be beneficial. BioClin has completed a 6-month dosing study in juvenile monkeys and they are conducting further studies to advance this program.

pipeline bioclin

Credits: http://www.bioclintherapeutics.com/pipeline.html

More information about B-701 can be obtained through the results from the B-701 oncology clinical trial, now entering phase 2.

High perspectives for B-701!

 

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