The Therapeutic Antibody Human Homology Project (TAHHP)

What?

The Therapeutic Antibody Human Homology Project is my attempt to group therapeutic monoclonal antibodies which have been used in human therapeutic trials according to their homologies with human germline immunoglobulin genes. My hope is that this will make it easier to identify whether there is any correlation between the efficacy of these antibodies (particularly regarding immune responses to the antibody) and the sequences of the variable regions.

Why?

Therapeutic antibodies these days are frequently classified as 'chimaeric', 'humanised', 'human' or 'fully human' antibodies. However my initial analysis of antibodies grouped this way identified that the name does not give a clear indication of how homologous to human sequences a therapeutic antibody is [see a summary of this data here]. This is because of conservation of immunoglobulin sequences between species.

Who?

The project is my own academic initiative prompted by my research and teaching interests in the field of therapeutic immunology. I intend to develop the project and publish the results on these web pages in a way which makes the data transparent to the reader and thus of use to the wider academic community. This project will be updated and continued as and when I can find time from my other teaching and research duties.

How?

The methodology I plan to use is very simple and has already been outlined in a review by Ed Routledge, Scott Gorman and myself published in 1993 ["Reshaping antibodies for therapy" Edward G. Routledge, Scott D. Gorman and Mike Clark, in Protein Engineering of Antibody Molecules for Prophylactic and Therapeutic Applications in Man pp.13-44 (1993) edited by Mike Clark publisher, Academic Titles, Nottingham, England ISBN 1 874695 00 8] and available on this website as an online readable source.

1. I intend to work only from therapeutic antibody sequences which are publically available and thus verifiable. Suitable sources are the scientific literature and published patents. Hopefully most sequences will be in electronic format and easily downloaded from the main databases.
2. After obtaining the sequences my initial analysis will be to quickly identify the Variable region sequences of the antibodies by reference to the immunoglobulin sequences from the Kabat and the IMGT databases and using the alignment resources from Andrew Martin.
3. Next I will run the V-region sequences against the V-Base directory which is available online (with registration) and which contains a listing of all of the identified human immunoglobulin germline gene segments. This resource also gives an indication of how common these different germline genes are in the human population. I plan to identify homologies for VH and JH segments and also for VK and JK or VL and JL separately. At present I plan to ignore identification of the the DH region sequence which contributes to the heavy chain CDR3. This is because of the difficulties of junctional diversity and N region diversity and also the multiple reading frames. For this reason the true homology of the heavy chain is likely to be a slight underestimate. The sequence comparisons are carried out on our University School of Biological Sciences Computer, 'mole', using the program TFASTA which allows a protein sequence to be run against translations of a DNA sequence database. I am grateful to the two administrators of mole, Jenny Barna and Erik Timmers, for setting up and managing the V-base database for use with TFASTA.
4. The sequence alignments will be used to prepare summary data and made available on this website.

Where?

You can find the results of the TAHHP analysis from the following links.

• Background to the project.
• TAHHP Antibody summaries.
• Selected sequence alignments.
• Complete search results for individual antibodies.

Can you Help?

This project requires that I identify the correct sequences which go along with each therapeutic antibody. Unfortunately most antibodies go through multiple name changes during their commercial development. This makes it rather time consuming to track the antibodies currently in trials back to the description of their original sequences. However if you are able to point me to details of a therapeutic antibody and it's sequence I will endeavour to include it in the list. Please remember that I only wish to include sequences and data which is in the public domain and readily verifiable as such. Also of value would be published details of antiglobulin responses to these antibodies and I will eventually try to cross reference this data.

• Some Antibodies in Clinical Development

You can email me as mrc7@cam.ac.uk

Links to Relevant Online Resources

• Kabat The Kabat Database of sequences of immunological interest.
• IMGT ImMunoGeneTics database(Montpellier France).
• V-Base A collection of human V-region databases from the MRC CPE (requires registration)
• Andrew Martin's Antibody Structure and Sequence Information Andrew Martin provides a thorough description of the numbering of immunoglobulin sequences and on the definition of CDRs.

Requests for this page since the counter was last reset.

This page is from Mike Clark
"An antibody engineer who also enjoys the mountains."
mrc7@cam.ac.uk
Mike's home-page

---

© Mike Clark, PhD., Cambridge University, UK
Last updated on 15th March 2000