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
Sortase handles allow for easy molecular assembly
Ingram, Schmidt, Ploegh. Exploiting Nanobodies’ Singular Traits. Ann Rev Imm 2018
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 stains CD47 brightly on many hematopoietic tissues
Sockolosky JT*, Dougan M* et al. PNAS 2016
A4
aCD47
B16 engineered to secrete A4 locally + anti-tumor Ab leads to near complete survival
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
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
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