Generation of a Half-Life Extended Anti-CD19 BiTE® Antibody Construct Compatible with Once-Weekly Dosing for Treatment of CD19-Positive Malignancies
2017
CD19is an immunoglobulin family member expressed ubiquitously on B cell lineage cells, from the pre-B cell to the mature B cell stage, until downregulation during terminal differentiation into plasma cells.
CD19is important for B cell activation, maturation and proliferation, and is widely expressed on the majority of B cell neoplasms. The T cell engaging bispecific antibody construct (
BiTE® )
blinatumomab, which targets
CD19, is approved for the treatment of relapsed or refractory B cell precursor acute lymphoblastic leukemia in adults and children in the US and has shown great promise for treating other
CD19-positive hematological malignancies. The short serum half-life of
blinatumomabnecessitates administration by continuous IV infusion to maintain therapeutic serum concentrations. To extend the half-life and allow for a more convenient administration, a next generation
BiTE® antibody construct designated
CD19HLE
BiTE® has been generated. The
CD19HLE
BiTE® comprises a new
CD19- and CD3-targeting tandem single-chain Fv antibody fused to an Fc domain. The biological properties of
CD19HLE
BiTE® were evaluated in vitro and in vivo .
CD19HLE
BiTE® binds with high affinity to both human and non-human primate (NHP)
CD19as well as CD3. In vitro experiments demonstrated that
CD19HLE
BiTE® can recruit and activate human and NHP T cells, mediating redirected lysis of
CD19-expressing cells at half-maximal effective concentrations in the low picomolar range. The fusion to an Fc domain resulted in a serum half-life of 210 hours following a single intravenous administration of a 5 µg/kg dose in NHP. In a repeat-dose study
CD19HLE
BiTE® caused robust depletion of circulating B cells, B lineage bone marrow cells, and peripheral lymphoid organ B cells in NHPs, whilst no overt signs of toxicity were observed in clinical and laboratory examinations of the animals. These results demonstrate that
CD19HLE
BiTE® effectively eliminated
CD19-positive cells in vitro and in vivo , and may be suitable for once weekly dosing in patients with
CD19-positive malignancies. Disclosures Lorenczewski: Amgen: Employment, Equity Ownership. Friedrich: Amgen Research (Munich) GmbH: Employment, Equity Ownership. Kischel: AMGEN: Employment. Dahlhoff: Amgen Research (Munich): Employment, Equity Ownership. Anlahr: Amgen: Employment, Equity Ownership. Balazs: Amgen Inc.: Employment, Equity Ownership. Rock: Amgen, Inc.: Employment, Equity Ownership. Boyle: Amgen: Employment. Goldstein: Amgen: Employment. Coxon: Amgen, Inc.: Employment. Chapman-Arvedson: Amgen, Inc.: Employment, Equity Ownership.
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