engineering il2-fc for cancer immunotherapy - informa connect
TRANSCRIPT
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Engineering IL2-Fc for cancer immunotherapy Daniel Christ Garvan Institute of Medical Research Sydney, Australia
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Rosenberg (2014)
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High dose IL-2 therapy
• Vascular leak syndrome (VLS): capillary leak leading to fluid accumulation
• Pulmonary oedema • Reduced organ perfusion (hypoxia of vital organs) • Intensive patient management required
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Interleukin-2 biology
• Pleiotropic
- Expansion of CD8+ T-cells and NK cells - Expansion of regulatory T-cells (Tregs)
Boyman and Sprent (2012)
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IL-2/anti-IL-2 antibody complexes
• Enhanced proliferation of CD8+ T-cells and NK cells
• Enhanced antitumour properties Boyman et al. 2006 Science, Krieg et al. 2010 PNAS
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IL-2 receptor structure
Boder 2012 Nature
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IL-2
CD122 CD132 CD25
Half-life extension via FcRn recycling
Steric blockade of CD25 binding site
IL-2/anti-IL-2 antibody complexes
Boyman et al. 2006 Science, Krieg et al. 2010 PNAS
Reduced renal clearance (> 50–60 kDa)
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Can we re-capitulate the effects of IL-2/mAb complexes within a single polypeptide chain?
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Mutant IL-2-Fc fusion proteins with superior activity and selectivity
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IL-2/anti-IL-2 antibody complexes
• CD8+ T-cells and NK cell proliferation ✔ • Antitumour properties ç Boyman et al. 2006 Science, Krieg et al. 2010 PNAS
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B16F10
IL-2WTFc displays high and unexpected anti-tumour activity
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Influence of immune effector functions
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IL-2WTFc targets Tregs for FcγR-dependent depletion
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Interactions with FcγR and CD25 are required for potent antitumour activity
B16F10
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CT26
Interactions with FcγR and CD25 are required for potent antitumour activity
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IL-2WTFc mediates Treg depletion in tumour tissue
B16F10
PBS
IL-2W
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IL-23X Fc
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Treg
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PBS
IL-2W
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IL-23X Fc
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PBS
IL-2W
T Fc
IL-23X Fc
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Tumour
PBS Fc Fcnil PBS Fc Fcnil PBS Fc Fcnil
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B16F10
IL-2WTFc / antibody combination therapy results in superior efficacy
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Summary
1. Interleukin-2 (IL-2) is a pleiotropic cytokine with proven track record as a human therapeutic
2. IL-2/mAb complexes increase IL-2 in vivo activity
3. Engineered IL-2-Fc fusion proteins exceed the efficacy of IL-2/mAb complexes
4. Intriguingly, Treg depletion, rather than cytotoxic cell expansion, dominant mechanism of antitumour activity of IL-2-Fc
5. Future developments will require carefully balancing of effects on CD8+/NK cells and Tregs to achieve optimal therapeutic outcomes
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Rodrigo Vazquez-Lombardi, Claudia Loetsch, Daniela Zinkl, Jenny Jackson, Peter Schofield, Elissa K. Deenick, Cecile King, Tri Giang Phan, Kylie E. Webster, Jonathan Sprent and Daniel Christ (2017) Nature Communications 8:15373 Rodrigo Vazquez-Lombardi, Damien Nevoltris, Ansha Luthra, Peter Schofield, Carsten Zimmermann and Daniel Christ (2018) Nature Protocols accepted
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Acknowledgements Rodrigo Vazquez-Lombardi
Jonathan Sprent
Christ Lab Peter Schofield Jenny Jackson
David Langley Romain Rouet
Mahdi Zeraati Mahmoud Abdelatti
Ansha Malik Damien Nevoltris
Sprent Lab Kylie Webster Tri Giang Phan Claudia Loetsch Theresa Corpuz Joanna Warren