Development ofTherapeutic Antibodies Targeting Human Acute Myeloid Leukemia Stem Cells
Lead Research Organisation:
University of Oxford
Department Name: Weatherall Inst of Molecular Medicine
Abstract
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Technical Summary
Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow with strong
evidence for the critical involvement of self-renewing leukemia stem cells (LSC) in disease
pathogenesis. We and others have proposed that AML LSC must be eradicated to achieve cure,
yet these cells are resistant to standard chemotherapy and radiation treatments. Our approach
to the development of novel AML therapeutics is to produce therapeutic antibodies directed
against cell surface antigens preferentially expressed on clinically relevant AML stem cells. We
identified and validated LSC-preferential expression of CD47, CD96, CD97, and TIM3 using
antigen-specific monoclonal antibodies. CD47 functions as a ?don?t eat me? signal by binding to
SIRP.. on phagocytic cells and delivering a dominant inhibitory signal. We determined that a
blocking anti-CD47 monoclonal antibody targets and depletes LSC in a mouse
xenotransplantation model by enabling their in vivo phagocytosis and elimination. We propose
to develop a clinical grade therapeutic antibody through the following aims:
(1): To define the surface marker expression of clinically relevant AML LSC in serial bone
marrow samples from patients enrolled in the UK NCRI AML 16 and 17 trials
(2): To develop humanized blocking monoclonal antibodies directed against human CD47
(3): To develop humanized recombinant monoclonal and/or bi-specific antibodies targeting
CD47 in combination with other AML LSC-specific proteins
(4): To develop a GMP grade antibody from the best candidate, including pre-clinical
toxicokinetic studies and large-scale production, and submit an IND filing with the FDA/MHRA
evidence for the critical involvement of self-renewing leukemia stem cells (LSC) in disease
pathogenesis. We and others have proposed that AML LSC must be eradicated to achieve cure,
yet these cells are resistant to standard chemotherapy and radiation treatments. Our approach
to the development of novel AML therapeutics is to produce therapeutic antibodies directed
against cell surface antigens preferentially expressed on clinically relevant AML stem cells. We
identified and validated LSC-preferential expression of CD47, CD96, CD97, and TIM3 using
antigen-specific monoclonal antibodies. CD47 functions as a ?don?t eat me? signal by binding to
SIRP.. on phagocytic cells and delivering a dominant inhibitory signal. We determined that a
blocking anti-CD47 monoclonal antibody targets and depletes LSC in a mouse
xenotransplantation model by enabling their in vivo phagocytosis and elimination. We propose
to develop a clinical grade therapeutic antibody through the following aims:
(1): To define the surface marker expression of clinically relevant AML LSC in serial bone
marrow samples from patients enrolled in the UK NCRI AML 16 and 17 trials
(2): To develop humanized blocking monoclonal antibodies directed against human CD47
(3): To develop humanized recombinant monoclonal and/or bi-specific antibodies targeting
CD47 in combination with other AML LSC-specific proteins
(4): To develop a GMP grade antibody from the best candidate, including pre-clinical
toxicokinetic studies and large-scale production, and submit an IND filing with the FDA/MHRA
Organisations
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ORCID iD |
| Paresh Vyas (Principal Investigator) |