CD19 binding molecules and uses thereof
Inventors
Granda, Brian • Rayo, Amy • HONG, Connie • Chelur, Dattananda • Lu, Haihui • CEBE, Regis • Jang, Sunyoung
Assignees
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Publication Number
US-12221481-B2
Publication Date
2025-02-11
Expiration Date
Abstract
The present disclosure provides CD19 binding molecules that specifically bind to CD19, including monospecific, bispecific and trispecific binding molecules, conjugates comprising the CD19 binding molecules, and pharmaceutical compositions comprising the CD19 binding molecules and the conjugates. The disclosure further provides methods of using the C19 binding molecules to treat diseases and disorders associated with expression of CD19. The disclosure yet further provides recombinant host cells engineered to express the CD19 binding molecules and methods of producing the CD19 binding molecules by culturing the host cells under conditions in which the CD19 binding molecules are expressed.
Core Innovation
A CD19 binding molecule specifically binds to human CD19 and comprises an antibody or antigen-binding fragment thereof, including defined CDR-H1, CDR-H2, and CDR-H3 amino acid sequences and defined CDR-L1, CDR-L2, and CDR-L3 amino acid sequences. The disclosure also includes CD19 binding molecules defined by fixed three-polypeptide sequence compositions.
The disclosure further covers multispecific binding molecule frameworks, including trispecific binding molecule (TBM) architectures in which ABM1 binds specifically to human CD19, ABM2 binds specifically to CD3, ABM3 binds specifically to human CD2, and an Fc domain is included. Additional CD3-binding antigen-binding module options and sequence-defined variants are described, together with higher-valency structural variants and ABM sequence options tied to the referenced tables.
Fc engineering is described for Fc-containing CD19 binding molecules to modulate Fc receptor and complement interactions and to improve multispecific Fc behavior. The disclosure includes FcRn-binding-lowering substitutions, variants designed to increase FcγRIIb binding and decrease FcγR binding broadly, FcγR ablation/silencing/FcKO variants that ablate FcγRIIIa binding to reduce ADCC while generally not affecting FcRn binding, complement C1q-binding reduction strategies, and Fc disulfide architecture modifications including heterodimerization strategies and CH3-domain knobs-into-holes, skew variants, pI variants, and polar-bridge/cysteine-pair options.
Claims Coverage
The independent claims cover sequence-defined CD19-binding molecules, trispecific CD19/CD3/CD2 binding molecules with an Fc domain, and CD19-binding molecules defined by fixed three-polypeptide compositions. Across the claims, there are four inventive features that specify CD19-binding CDR sequence identities, trispecific ABM module composition targeting CD3 and human CD2, and particular three-polypeptide sequence compositions for CD19 binding molecules.
Human CD19-specific CDR-defined antibody or antigen-binding fragment
A CD19 binding molecule that specifically binds to human CD19 and comprises an antibody or antigen-binding fragment comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively, and CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO:17, SEQ ID NO:18, and SEQ ID NO:19, respectively.
Trispecific binding molecule with CD19, CD3, human CD2, and an Fc domain
A CD19 binding molecule which is a trispecific binding molecule (TBM) comprising an ABM1 Fab that binds specifically to human CD19 with CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6 and CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO:17, SEQ ID NO:18, and SEQ ID NO:19; an ABM2 that binds specifically to CD3 comprising SEQ ID NO:174 or SEQ ID NO:189; an ABM3 that binds specifically to human CD2 comprising SEQ ID NO:327; and an Fc domain.
Three-polypeptide CD19 binding molecule defined by SEQ ID NO:1077, SEQ ID NO:759, and SEQ ID NO:1078
A CD19 binding molecule comprising a first polypeptide with an amino acid sequence comprising SEQ ID NO:1077, a second polypeptide with an amino acid sequence comprising SEQ ID NO:759, and a third polypeptide with an amino acid sequence comprising SEQ ID NO:1078.
Three-polypeptide CD19 binding molecule defined by SEQ ID NO:1077, SEQ ID NO:759, and SEQ ID NO:1086
A CD19 binding molecule comprising a first polypeptide with an amino acid sequence comprising SEQ ID NO:1077, a second polypeptide with an amino acid sequence comprising SEQ ID NO:759, and a third polypeptide with an amino acid sequence comprising SEQ ID NO:1086.
Overall, the independent claims cover human CD19-binding antibodies or antigen-binding fragments defined by specified CDR amino-acid sequences, trispecific TBMs that add CD3 and human CD2 binding via specified ABM sequences plus an Fc domain, and CD19-binding molecules defined by fixed three-polypeptide sequence compositions.
Stated Advantages
Reduces ADCC by ablation of FcγRIIIa binding while generally not affecting FcRn binding.
Reduces C1q binding via Fc substitutions for complement pathway reduction.
Improves multispecific Fc behavior through Fc receptor and complement interaction modulation.
Improves heterodimer yield/pairing using Fc heterodimerization strategies including CH3-domain knobs-into-holes and related skew/pI/polar-bridge/cysteine-pair options.
Improved ADC stability.
Reduced DAR loss.
Improved thermal stability in CD58 disulfide variants while maintaining CD2 binding affinity and stoichiometry.
Mitigation of cytokine release syndrome (CRS) and macrophage activation syndrome/HLH (MAS) by targeting soluble cytokines.
Achieving optimal T-cell activation while reducing exhaustion through CD2 co-stimulation via a CD58 moiety.
Documented Applications
Used as multispecific Fc behavior and Fc-containing CD19 binding molecules, including multispecific binding molecules and trispecific binding molecules (TBM) with ABMs targeting CD19, CD3, and CD2.
Therapeutic use for CD19-expressing diseases, including hematologic cancers such as leukemia and lymphoma.
Combination therapy regimens using CD19 ADCs together with additional agents, including thalidomide/lenalidomide/pomalidomide derivatives and other classes of agents.
Conjugation of CD19 binding molecules to detectable/diagnostic agents, including fluorescent materials, radioactive materials, and immunoassays.
Use of CD19 binding molecules attached to solid supports.
Pharmaceutical composition formulation for therapeutic use, including companion diagnostic contexts.
CD19 binding molecule ADC linker architectures that couple to cytotoxic and/or cytostatic agents using enzymatically cleavable lysosomal peptides.
ADC linker architectures addressing drug derivative release for non-cleavable linkers via lysosomal degradation to amino acids, with considerations of stability and aggregation.
Anti-tumor activity in humanized mouse models.
Functional use in redirected T-cell cytotoxic activity (RTCC), T-cell proliferation, and cytokine secretion readouts, including CD2-dependent activation.
T-cell engaging cancer treatment using CD19-binding bispecific/trispecific molecules (MBMs/TBMs), together with co-administration of agents for toxicity management (CRS and HLH/MAS).
Functional characterization of CD19 binders NEG218 and NEG258, including RTCC against CD19+ target cell lines, T-cell proliferation, CD2-dependent activation using CD2-KO effectors, and cynomolgus cross-reactive binding and ex vivo cyno B-cell depletion/activation readouts.
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