Treatment of Protein Misfolding Diseases with Novel Biologics

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Presentation transcript:

Treatment of Protein Misfolding Diseases with Novel Biologics Dr. Mourad Tayebi D.V.M (Hons) M.Sc Ph.D Senior Lecturer; University of Surrey / Founder and CSO; PrioCam LLC (USA) International Congress on Neuroimmunology and Therapeutics July 20-22, 2015 San Francisco, California, USA

“While current drug therapies only treat the symptoms of Alzheimer's disease, researchers have great hope that in the near future there will be treatments that can stop or slow Alzheimer's” ALZHEIMER’S ASSOCIATION

Conventional Antibodies (BCTDI)

The immunoglobulin molecule, IgG, is built up from two copies each of two different polypeptide chains, heavy (H) and light (L).

Do conventional antibodies inhibit prion replication in vivo ?

NMR PrP121-231 b-PrP? C N G. Jackson MRC Prion Unit Riek et al, Nature 1996 b-PrP? G. Jackson MRC Prion Unit C N

Immunization Protocol

Conventional mAbs inhibit prion replication and delay the onset of prion disease White et al. Nature 2003

PrPC-specific antibody triggers neuronal apoptosis Solforosi et al. Science 2004 IgG P (95-105) IgG D13 (95-105) IgG b12 (HIV-1)

PROBLEMS TO OVERCOME: BBB crossing Cell penetration Brain diffusion Toxicity And Serum half life Immunogenecity We knew we needed: Different type of antibodies We also needed a way to stabilize the proteins prior to immunization

Next Generation Antibody Technology Unconventional Antibody!!

Conventional antibodies and derived fragments

Two heavy chains with no light chain. Camelid antibodies – Single-Domain - VHH Two heavy chains with no light chain. Lack the CH1 domain Smaller size, Greater solubility Higher stability Hamers-Casterman et al., 1993 Dumoulin et al., 2002

PRIOV ANTIBODIES

Unconventional antibodies and derived fragments

Quality of immune response is time- and conformation-dependent Tayebi & Hawke personal communication

Treatment of prion diseases with conventional antibodies Tayebi et al. Mol Med 2004 – Patent N

Camelid antibodies enter the cell membrane Jones al. PLoS ONE 2010 & Patent

BBB transmigration of camelid antibodies

PrP-specific transmigration of camelid antibodies across the BBB in vitro siRNA PI-PLC David et al. J Neuroimmunol 2014

PrP-specific transmigration of camelid antibodies across the BBB in vitro David et al. J Neuroimmunol 2014

Bio distribution of camelid antibodies in brain and tissues (i.p.) David et al. J Neuroimmunol 2014

Camelid antibodies are not toxic to N2a Jones al. PLoS ONE 2010

Do unconventional antibodies inhibit prion replication in vivo ?

Anti-PrP VHH permanently abrogates prion replication in cell lines, spleen and brain Jones al. PLoS ONE 2010 & unpublished

Immunodetection of Aβ1-40, Aβ1-42 & tau1-16 with camelid antibodies David et al. J Neuroimmunol 2014

Immunodetection of Aβ and tau oligomers In brain of AD patients Tayebi & David unpublished

Do unconventional antibodies inhibit Aβ plaque formation in vivo ?

Reduction of Aβ plaque burden following treatment with camelid anti-Aβ1-42 antibody Tayebi & David unpublished

Reduction of Ab soluble oligomer following treatment with camelid antibody Tayebi & David unpublished

Conventional Antibodies (BCITDI and not BCTDI)

Toxic Soluble Oligomers Soluble Amyloid Oligomers are a Common Intermediate in Amyloid Fibril Formation. Toxic Soluble Oligomers Glabe &Tayebi & David unpublished

Immunodetection of Soluble Oligomers with anti-prion-oligomer mAbs Tayebi al. PLoS ONE 2012

Opportunities for Therapeutic and Diagnostic Development Diabetes Type II Alzheimer’s Disease Mad Cow’s Disease Parkinson’s Disease Huntington’s Disease Serum amyloidosis Cancer Vaccine Drug Discovery Diagnostic ☻ ☻ ☻ ☻ ☻ ☻ X? ☻ ☻ X? ☻ ☻ ☻ ☻ ☻ ☻ ☻ ☻ ☻ ☻ X?

General antibody market BCC Research Report on Monoclonal Therapeutics and Diagnostic Imaging

Annual sales of monoclonal antibody products BCC Research Report on Monoclonal Therapeutics and Diagnostic Imaging

Selected ADCs in clinical development BCC Research Report on Monoclonal Therapeutics and Diagnostic Imaging

Next Generation Antibodies: Future Market Prospect

Acknowledgments RVC London Monique David Daryl Rhys Jones William Taylor Benjamin Stileman Umaymah Hewitt Martin Smith Liam Good Imperial London Steve Gentleman Richards Reynolds IOO London John Greenwood USYD Simon Hawke