The importance of inducing an adaptive response Stephanie Dougan Michael Dougan Dana-Farber Cancer Institute Department of Cancer Immunology and Virology Harvard Medical School Department of Immunology
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
The importance of inducing an adaptive response
Stephanie DouganMichael Dougan
Dana-Farber Cancer InstituteDepartment of Cancer Immunology and Virology
Harvard Medical SchoolDepartment of Immunology
VHH Antibodies
Small size (15 kDa) allows deep tissue penetration
Rapidly cleared after injection
Antibody targets: PD-L1, MHC class II, CD11b, CTLA-4, Tim3, CD47, CD8, PD-1, VISTA
Cross-reactive with human, or human-specific versions available
Phase II trial of a humanized VHH showed very little immunogenicity
Collaboration with Hidde Ploegh
Finding VHHs from live camelids by phage display
Sortase handles allow for easy molecular assembly
Ingram, Schmidt, Ploegh. Exploiting Nanobodies’ Singular Traits. Ann Rev Imm 2018
VHH against murine CD47
Sockolosky JT*, Dougan M* et al. PNAS 2016
VHH against murine CD47
Sockolosky JT*, Dougan M* et al. PNAS 2016
Mouse CD47 Human CD47
A4 blocks binding of CD47 to mSIRPα
Sockolosky JT*, Dougan M* et al. PNAS 2016
A4 outperforms miap301
Sockolosky JT*, Dougan M* et al. PNAS 2016
A4 augments phagocytosis by the anti-B16 antibody TA99
Bone marrow derived macrophages cultured with CFSE labeled B16 cells for 2 hours
A4 augments phagocytosis of hEGFR-CT26 cells
Bone marrow derived macrophages cultured with CFSE labeled hEGFR-CT26 cells for 2 hours
A4 augments phagocytosis of via IFN-inducible PD-L1
Bone marrow derived macrophages cultured with CFSE labeled B16 cells for 2 hours
A4 augments phagocytosis of Tregs via CTLA-4
A4 stains CD47 brightly on many hematopoietic tissues
Sockolosky JT*, Dougan M* et al. PNAS 2016
A4
aCD47
A4 alone does not cause anemia
CD47-IgG2a “microbody” as a model for anemia irAE
Ingram JR et al. PNAS 2017
A4 synergizes with PD-1 blockade in B16 melanoma
Ingram JR et al. PNAS 2017
CT26 model is non-responsive
Ingram JR et al. PNAS 2017
B16 melanoma
Underwhelming performance of A4
Ingram JR et al. PNAS 2017
Underwhelming performance of A4 – inefficient blockade of CD47?
Ingram JR et al. PNAS 2017
B16 engineered to secrete A4 locally – blocks its own CD47 in vitro
Ingram JR et al. PNAS 2017
B16 engineered to secrete A4 locally – blocks its own CD47 in vivo
Ingram JR et al. PNAS 2017
B16 engineered to secrete A4 locally + anti-tumor Ab leads to near complete survival
Ingram JR et al. PNAS 2017
Vaccination can supply anti-tumor antibodies
Ingram JR et al. PNAS 2017
Possible role for Treg phagocytosis
Ingram JR et al. PNAS 2017
Concluding thoughts part I
Cross-linking of red blood cells can lead to fatal anemia – may be dependent on epitope positioning
Near complete coverage of CD47 is required for efficacy in melanoma – better local delivery is needed
Synergy with multiple antibodies including anti-PDL1 (IFN-inducible), anti-CTLA4 (Tregs), polyclonal Abs from vaccination
Role for engagement of Sirpα on other cell types
Heckler and Dougan, Gastroenterology 2018
Productive immunity is polyfunctional
Acknowledgements
Stephanie and Michael Dougan lab: Kevin Roehle, Eleanor Clancy-Thompson, Lestat Ali, Tamara Biary, Stephanie Crowley, Daniel Heid, Katherine Ventre, Max Heckler, Aladdin Bhuiyan, Patrick Lenehan, Gui Zhen Chen, Jana Tegethoff, Patrick Bruck, Jessica Ingram
BRIDGE project
Hidde Ploegh
Chris GarciaJonathan Sockolosky
David Knipe Steve AlmoMichael Walsh
Related Documents
