Bi-specific monovalent diabodies that are capable of binding CD19 and CD3, and uses thereof
Inventors
Johnson, Leslie S. • Bonvini, Ezio • Lam, Chia-Ying Kao • Moore, Paul A. • Liu, Liqin • Koenig, Scott
Assignees
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Publication Number
US-11639386-B2
Publication Date
2023-05-02
Expiration Date
Abstract
CD19×CD3 bi-specific monovalent diabodies, and particularly, CD19×CD3 bi-specific monovalent Fc diabodies, are capable of simultaneous binding to CD19 and CD3, and are used in the treatment of hematologic malignancies.
Core Innovation
The invention provides a CD19×CD3 bi-specific Fc diabody that specifically binds to CD19 and to CD3. The Fc diabody is a covalently bonded complex formed by a first, a second and a third polypeptide chain, with binding mediated by VL and VH domains for CD19 and CD3 and Fc functionality provided by CH2–CH3 domains that bind to an Fc receptor.
A particular polypeptide architecture is used, in which Domain IA and Domain IIA include sub-domains with VL and VH domains separated by polypeptide linkers, thereby forming monovalent CD19 binding domains and monovalent CD3 binding domains. Domain IB and Domain IIB include charged helical domains with opposite charges, and the CH2–CH3 domains of the first and third polypeptide chains form an Fc domain.
In the treatment method, the CD19×CD3 bi-specific Fc diabody is administered to a subject for a hematologic malignancy associated with the expression of CD19. The diabody is further defined by specific amino acid sequence assignments for VL/CD19, VH/CD19, VL/CD3, and VH/CD3, and by particular charged helical domain sequence options provided by SEQ ID numbers.
Claims Coverage
The provided material contains three independent claims. The main inventive features include a treatment claim for a CD19-associated hematologic malignancy and two claim categories directed to polynucleotides and a host cell.
Treating CD19-associated hematologic malignancy with a three-chain covalently bonded CD19×CD3 bispecific Fc diabody
A method of treating a hematologic malignancy associated with expression of CD19 by administering a CD19×CD3 bi-specific Fc diabody that specifically binds to CD19 and to CD3, wherein the diabody comprises a first, a second and a third polypeptide chain forming a covalently bonded complex, with defined Domain IA/IB/IC, Domain IIA/IIB, and Domain IIIC arrangement and with CH2–CH3 domains forming an Fc domain that binds to an Fc receptor.
Polynucleotide encoding specified sequences
A polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO:35 or SEQ ID NO:37.
Host cell containing polynucleotides encoding specified sequences
A host cell comprising a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO:35, a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO:37, and a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO:39.
Claim coverage spans administering the specified CD19×CD3 bispecific Fc diabody via a three-chain covalently bonded complex with defined domain architecture, plus genetic constructs and a host cell defined by polynucleotides encoding polypeptides with amino acid sequences corresponding to SEQ ID NO:35, SEQ ID NO:37, and SEQ ID NO:39.
Stated Advantages
The diabody shows redirected killing of CD19+ B lymphoma lines with no killing of CD19-negative controls and no killing with monospecific control diabodies.
The diabody depletes autologous B cells in human and cynomolgus monkey PBMCs.
The diabody induces T-cell activation markers and upregulates granzyme B and perforin.
The nonclinical findings report complete or near-complete tumor control in multiple xenograft models.
The characterization summary reports an asserted safety margin based on EC50 differences versus cytotoxicity.
Documented Applications
Treatment of a hematologic malignancy associated with the expression of CD19 in a subject in need thereof.
Use against CD19+ B lymphoma lines.
Use in xenograft co-mix and established tumor models.
Use in PBMC-reconstituted NSG mouse models.
Use with malignant B cells from CLL primary patient samples.
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