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The latest news from the Rabbitts Group.

Intracellular Antibody Capture Technology

The intracellular antibody capture technology (IACT) has been updated using improved screening protocols and focussed on single domain antibody fragments (iDAbs). This allows rapid isolation of iDAbs that can be used to block intracellular functions, such as protein-protein interactions, and to use this for target validation in diseases. Thus target validation can be achieved with intracellular antibody fragments prior to drug development programmes (to avoid the latter being undertaken prior to target validation).

Protocol Exchange (2018)              DOI:  http://dx.doi.org/10.1038/protex.2018.007
The selection of single-domain antibody fragments (iDAbs) by intracellular antibody capture in yeast

Summary
The ability to screen for intracellular antibody fragments inside yeast cells has been an important method to obtain single chain Fv (scFv) and intracellular domain antibodies (iDAbs) that express in the reducing environment of cells. The method was originally called Intracellular Antibody Capture (IAC) and, because it is a two hybrid-based method, it does not require immunisation of animals and does not require purified recombinant proteins to elicit an in vivo immune response or for other methods such as phage selection. The IAC method can be used to obtained intracellular antibodies to self-antigens and to conserved antigens. The new Protocol Exchange article sets out the most recent amendments to our screening protocol and tips for best practise.

New book publication on Chromosomal Translocations 

A book edited by Janet Rowley, Michelle Le Beau and Terry Rabbitts called “Chromosomal Translocations and Genome Rearrangements in Cancer” has recently been published (Springer).

Rowley book cover[1]

The multi-author book describes the discovery and characterization chromosomal translocations and aberrations in wide range of cancer types and the aim of the book is to facilitate development of better cancer diagnostics and treatments by informing academic and clinical scientists about the work on aberrant cancer genomes.

The volume was stimulated by work on genome organization from the first cloning of chromosomal translocations in the 1980s to current deep sequencing of cancer genomes. The first chromosomal translocation to be described as somatically acquired in a cancer cell was the Philadelphia chromosome found by Nowell and Hungerford in 1960. Chromosome banding techniques introduced in the 1970s allowed the elucidation of many more recurrent chromosomal abnormalities in cancer cells. The first molecular cloning of chromosomal translocation breakpoints was from the Philadelphia chromosome and from Burkitt’s lymphoma translocations, in the early 1980s. These studies laid the foundation for detection of many gene fusions in cancer as well as oncogene activation in lymphoid tumour chromosomal translocations. Breakpoint cloning and next generation deep sequencing has led to the detection of more than 1,300 different cancer-associated gene fusions.

Cancer genome characterization had reached a zenith by about 2010 that led the book’s Editors to conclude that the details of chromosomal abnormalities in most cancer types was well established and the volume therefore would be timely.

 

Orbit Discovery

A new spin out company focussing on therapeutic peptides

Orbit Discovery – a new spinout from the University of Oxford – has been launched to use the technology developed at Oxford’s Weatherall Institute of Molecular Medicine by Professors Graham Ogg and Terence Rabbitts.

Orbit Discovery has raised seed funding to commercialise technology which will help to identify targeted, affordable therapeutic drugs known as peptides. Oxford Sciences Innovation, the £320m investment company established to provide capital and scaling expertise to Oxford spin-outs, is the lead investor in the new company.  Other investors include the Oxford Technology and Innovations EIS Fund led by George Robinson and the OT(S)EIS fund managed by Oxford Technology management, which has been making science investments around Oxford for 30 years.

Orbit Discovery will establish a screening platform to identify robust peptide drug candidates for both internal industry drug discovery programs and via collaborative research. Enquiries for commercial collaborations or licencing opportunities should be directed to the CEO Dr Alex Batchelor.

 

Clotten Foundation Prize 2015

Professor Terry Rabbitts has been awarded the inaugural Clotten Foundation Prize 2015 for discoveries on human antibody genes leading to therapeutic antibodies, and discoveries on chromosomal translocations in cancer leading to novel therapeutic approaches.

The Clotten Foundation was founded in 1994 following the death of Dr Annemarie Clotten, who bequeathed an endowment to establish the organisation. The Clotten Foundation aims to support cancer research that particularly benefits children with malignancies. The Foundation awards a prize every two years to an established scientist who

has contributed in a unique way to the understanding and treatment of cancer with a particular emphasis on children.

LMO2 at 25 years 

25 years ago, the LMO2 gene was discovered near areas of chromosome damage in human blood cells, leading to cancer. LMO2 has since become a paradigm of a cancer gene caused by chromosome damage. It was also found to cause cancer in gene therapy trials involving bone marrow transplantation. Normally, LMO2 is an essential protein that performs critical functions in the development of the blood cells and some aspects of blood vessel formation while it has also recently been used as part of a mixture of proteins to create artificial stem cells. LMO2 is both a key-player in stem cell medicine and also a target for anti-cancer therapies.  There is potential for therapeutic targeting in diseases where angiogenic processes are involved such as diabetic retinopathy.

A recent review has been published summarizing much of what is known about LMO2.

See:

http://www.ncbi.nlm.nih.gov/pubmed/26108219
http://www.imm.ox.ac.uk/lmo-genes-and-proteins

 

Intracellular Antibody Capture

Intracellular antibody capture (IAC) was developed to select antibody fragments that function in the reducing environment of cells and recognize native proteins (1, 2). Recent work has enhanced this method to simplify the IAC selection process while retaining the key feature of intracellular screening of diverse single domain libraries (3). 

1. Tanaka, T., Rabbitts, T.H. (2010) Nature Protocols 5:1, 67-92

2. Zhang, J., Rabbitts, T.H. (2014) BBA - Proteins and Proteomics 1844, 1970-1976

3. Zeng, J., Li, H.H., Tanaka, T., Rabbitts, T.H. (2015) Selection of human single domain antibodies recognizing the CMYC protein using enhanced intracellular antibody capture
Journal of Immunological Methods 

EPSRC Programme Grant to Support New Oxford Centre for Drug Delivery Devices


Our group will be part of the new Oxford Centre for Drug Delivery Devices, starting in July 2014, to develop new methods for drug delivery. The new Centre has been funded by a £10.1 million Programme Grant that includes £6.4 million from the Engineering and Physical Sciences Research Council (EPSRC).

New generation techniques have produced many macromolecules (e.g. antibody fragments) that function in the intracellular environment and these have potential to be drugs but the limitation is in delivering the macromolecules* to their site of action. The new funding will allow us to interact with experts in the Oxford Centre working with new drug delivery techniques to implement clinical delivery of our high affinity antibody fragments for cancer treatment.

* we call macromolecular drugs, macrodrugs to distinguish from conventional small molecule drugs

 See also http://www.imm.ox.ac.uk/major-epsrc-programme-grant-to-support-new-oxford-centre-for-drug-delivery-devices

 

Student Visit 

A group of undergraduate students studying human biosciences at Petroc, a further education college in north Devon, were invited to visit the THR lab & the WIMM on the 19th January 2015.

Students from the FdSc Human Bioscience spent a day at the Weatherall Institute of Molecular Medicine (WIMM), hosted by Dr Peter Canning, visiting Professor Rabbitts’ lab to hear about their research into how antibodies could be used as healthcare tools.

The day activities included meeting with Steve Taylor who gave a talk about Bioinformatics at WIMM , hearing about the role of iron in human immunity studies (by Professor Hal Drakesmith) and learning about research into regenerative medicine using zebrafish. This was followed by a visit to the Wolfson Imaging Centreand a visit to the Flow Cytometry facility.

The students appreciated the opportunity to see equipment that is not available in a classroom, as well as to gain an insight into the work of WIMM scientists. One second year student, Kerry, said: “The day has been inspirational – so many things to think about.”