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Publication Number
US-11180563-B2
Publication Date
2021-11-23
Expiration Date
Abstract
Provided herein are FLT3 binding proteins, pharmaceutical compositions comprising such proteins or fragments thereof, as well as nucleic acids, recombinant expression vectors and host cells for making such FLT3 binding proteins. Also disclosed are methods of using the disclosed FLT3 binding proteins in the prevention, and/or treatment of diseases, conditions and disorders.
Core Innovation
The invention relates to FLT3 binding proteins constructed from single-domain FLT3 binders and FLT3 binding domains comprising at least three complementarity determining regions, a CDR1, a CDR2, and a CDR3, with specified sequence identifiers. The disclosed FLT3 binding domain uses CDR1 SEQ ID NO: 91, CDR2 SEQ ID NO: 149, and CDR3 SEQ ID NO: 195, and includes framework region variants defined by sequence identity and variant ranges.
The document describes FLT3 targeting multispecific proteins, including bispecific and trispecific anti-FLT3/anti-CD3 and anti-FLT3/anti-CD3/anti-ALB architectures. Human CD3 is used in these formats, and the document specifies domain orientation and arrangement constraints, including single-chain polypeptide formats with specified domain joins and domain arrangement across the N-terminus and C-terminus.
The document further describes conditionally active ProTriTAC/Protrispecific formats for FLT3 targeting, using masking moieties and albumin-binding together with protease-cleavable linkers. The constructs are framed as FLT3 targeting proteins with serum albumin association and half-life extension concepts, and the document also includes pharmaceutical compositions, recombinant production concepts, and FLT3 diagnostic/monitoring kits using anti-FLT3 single-domain antibodies.
Therapeutic use is described broadly for FLT3-associated hematologic malignancies including acute myeloid leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia, and additionally for other cancers. The document also describes use cases for neoplastic conditions, spanning solid tumors, melanoma, and hematologic malignancies, in front-line, relapsed/refractory, recurrent, maintenance therapy, prophylactic/adjuvant use, and prevention of peri-surgical metastasis.
Claims Coverage
The consolidated claim coverage provides two independent claims. Together they define FLT3-binding domains with specified CDR sequence identities and an FLT3-targeting trispecific protein that binds human CD3, human serum albumin, and human FLT3.
Specified FLT3 binding domain CDR sequences
An FLT3 binding domain comprising at least three complementarity determining regions, a CDR1, a CDR2, and a CDR3, wherein the CDR1 comprises SEQ ID NO: 91, the CDR2 comprises SEQ ID NO: 149, and the CDR3 comprises SEQ ID NO: 195.
Human CD3, serum albumin, and FLT3 trispecific protein
An FLT3 targeting trispecific protein comprising a first domain that binds a human CD3, a second domain that binds a human serum albumin protein, and a third domain that binds a human FLT3, wherein the third domain comprises a CDR1 comprising SEQ ID NO: 91, a CDR2 comprising SEQ ID NO: 149, and a CDR3 comprising SEQ ID NO: 195.
Overall, the claims cover FLT3-binding domains defined by specific CDR sequence identifiers SEQ ID NO: 91, 149, and 195, and their use within multispecific or trispecific proteins that bind human CD3 and human serum albumin in addition to human FLT3.
Stated Advantages
In vivo antitumor efficacy with tumor growth reduction versus control.
Tumor regression.
Ability to target and treat neoplastic conditions including solid tumors and hematologic malignancies.
Conditionally active ProTriTAC/Protrispecific activity is described using masking via albumin-binding and protease-cleavable linkers.
Half-life extension is described in connection with albumin binding and serum albumin association concepts.
Functional potency is described using TDCC EC50 values.
Ability to detect FLT3 expression via kits and labeled anti-FLT3 single-domain antibodies using direct and competition immunoassay formats.
Documented Applications
Treating neoplastic conditions in a front-line setting.
Treating neoplastic conditions in relapsed/refractory settings.
Treating recurrent neoplastic conditions.
Maintenance therapy for neoplastic conditions.
Prophylactic/adjuvant use for neoplastic conditions.
Preventing peri-surgical tumor metastasis.
Treating acute myeloid leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia.
Treating other cancers.
Pharmaceutical compositions for the disclosed FLT3 binding proteins.
Recombinant production of the disclosed proteins.
Detecting and diagnosing FLT3 expression using FLT3 expression detection kits and labeled anti-FLT3 single-domain antibodies in direct and competition immunoassay formats.
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