Abstract Book 2010 - CIMT Annual Meeting

062 Ashfield | New targets & new leads
ImmTACs: bi-functional reagents for redirected tumour
cell killing
Rebecca Ashfield 1 , Linda Hibbert 1 , Nathaniel Liddy 1 , Giovanna Bossi 1 , Katherine Adams 1 ,
Anna Lissina 2 , Tara Mahon 1 , Namir Hassan 1 , Jessie Gavarret 1 Frayne Bianchi 1 , Nicholas
Pumphrey 1 , Kristin Ladell 2 , Emma Gostick 2 , Andrew Sewell 2 , Nikolai Lissin 1 , Peter Molloy 1 ,
Yi Li 1 , Brian Cameron 1 , Malkit Sami 1 Emma Baston 1 , Penio Todorov 1 , Samantha Paston 1 ,
Rebecca Dennis 1 , Andy Johnson 1 , David Price 2 , Annelise Vuidepot 1 , Daniel Williams 1 , Bent
Jakobsen 1
1 Immunocore Ltd, 57C Milton Park, Abingdon, Oxfordshire, OX14 4RX UK
2 Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, Wales, UK
The human immune system can theoretically
identify malignant cells by inspecting cell surface
Class I HLA -peptide complexes for the presence of
disease-associated epitopes. Indeed, many cancer
patients generate CD8 cyto-toxic T cell responses
to tumour-associated antigens; the majority of patients,
however, fail to clear tumours since T cell
avidity for self-antigens tends to be weak, and
cancer cells employ escape mechanisms for avoiding
destruction by T cells. To overcome these
issues, we have engineered novel, bi-functional
protein therapeutics termed ImmTACs (Immune
Mobilising mTCR Against Cancer) which re-direct
the immune system to target and destroy tumour
cells with a high degree of potency and specificity.
An ImmTAC comprises a high affinity ‘monoclonal’
T cell Receptor (mTCR) targeting a cancer-associated
HLA-peptide complex, fused to an anti-CD3
scFv domain which activates an anti-tumour T cell
response.
We demonstrate that ImmTACs against a number
of different cancer-associated antigens can target
and kill tumour cells expressing as few as 5-20 epitopes
per cell with pico-Molar potency. ImmTACs
preferentially activate effector memory CD8 T cells,
resulting in secretion of multiple cytokines and
tumour cell killing; a single activated T cell can kill
multiple antigen positive tumour cells. Furthermore,
we demonstrate that the reagents are able to
inhibit tumour growth in mouse xenograft models.
In vitro ImmTAC potency translates to a dose of
less than 1mg in humans, representing a significant
advance over existing targeted anti-cancer therapies
including monoclonal antibodies.
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