Development of Manabodies to the R140Q mutant in IDH2

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Unmet Need
The immune system samples and recognizes the intracellular contents of cells (i.e., normal, abnormal, infected and cancer cells) through antigen processing via surface human leukocyte antigens (HLAs) and antigen presentation to T cells via T cell receptors (TCRs), all of which enables the body to distinguish self from non-self proteins. For example, a virally-infected cell would present viral peptides by its surface HLA, triggering T cells to kill that cell.  Similarly, in cancer cells, mutant peptides referred to as MANAs, “Mutation-Associated Neo-Antigens”, can be presented by HLA on the cancer cell surface enabling T cells to eliminate cancer cells.
Acute myeloid leukemia (AML) is characterized by abnormal myeloblasts that infiltrate the bone marrow and inhibit the body’s ability to undergo normal hematopoiesis. While up to 35-40% of AML patients can now be cured, a majority of patients, particularly older patients, succumb to their disease. Gene mutations in isocitrate dehydrogenase 2 (IDH2) are present in approximately 10% of AML, with one single mutation at codon 140 being by far the most common IDH2 mutation.
A therapy or diagnostic specifically targeting MANAs could therefore provide a tumor-specific method to diagnose or treat cancers, e.g., AML caused by mutant IDH2.
Technology Overview
Johns Hopkins researchers generated single chain variable fragments (scFvs) specific for mutant peptides presented on the cell surface by human leukocyte antigen (HLA) molecules. These scFvs can be converted to full-length antibodies, termed MANAbodies, targeting “Mutation Associated Neo-Antigens” bound to HLA. A phage display library representing a highly diverse array of single-chain variable fragment sequences was first designed and constructed. A competitive selection protocol was then used to identify clones specific for peptides bound to pre-defined HLA types. In this way, scFvs, including one specific for a peptide encoded by an IDH2 mutant (at codon 140) were generated. Molecules targeting MANA can be developed that specifically react with mutant peptide-HLA complexes even when these peptides differ by only one amino acid from the normal, wild-type form.
These findings suggest that MANAbodies can be converted to therapeutic agents such as a chimeric antigen receptor (CAR) for use in redirecting and activating T cells to kill tumor cells (CAR-T) expressing HLA and mutant IDH2 proteins.
Stage of Development
Preclinical data is available.
Skora AD et al. PNAS August 11, 2015. 112 (32) 9967-9972
Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date Patent Status
Development of Manabodies to the R140Q mutant in IDH2 PCT: Patent Cooperation Treaty PCT PCT/US2018/032996   5/16/2018     Pending
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Jeanine Pennington
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