Bispecific antibodies against CD3 and CD20 for treating chronic lymphocytic leukemia
Inventors
Elliott, Brian • CHEN, Jenny Jianlin • Ahmadi, Tahamtan • CHIU, Christopher W. L. • BREIJ, Esther C. W. • HIEMSTRA, Ida • JURE-KUNKEL, Maria N.
Assignees
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Publication Number
US-11858995-B2
Publication Date
2024-01-02
Expiration Date
Abstract
Provided are methods of clinical treatment of chronic lymphoblastic leukemia (CLL) in human subjects using a bispecific antibody which binds to CD3 and CD20.
Core Innovation
The invention relates to a method of treating chronic lymphocytic leukemia (CLL) in a human subject by subcutaneously administering a bispecific antibody. The bispecific antibody comprises a first binding arm that binds to human CD3ε and a second binding arm that binds to human CD20, with defined VH and VL region CDR sequences in specified SEQ ID NOs, or with specified heavy chain and light chain amino acid sequences.
The document characterizes epcoritamab as a DuoBody-CD3xCD20 bispecific antibody and defines engineered IgG1 Fc/CH3 mutations in the heavy chains. The IgG1 Fc/CH3 mutations include L234F, L235E, and D265A in both heavy chains, and complementary CH3 mutations F405L and K409R are included to enable controlled Fab-arm exchange.
A step-up subcutaneous treatment regimen in 28-day cycles is defined for CLL in a human subject. The regimen includes a priming dose on day 1 of cycle 1, an intermediate dose on day 8 of cycle 1, and subsequent full doses on later days in cycle 1, with continued full-dose administration at least until complete response, partial response, or stable disease, or until progressive disease develops or unacceptable toxicity occurs.
Claims Coverage
The document identifies three independent claims directed to methods of treating CLL with subcutaneous administration of a CD3ε/CD20 bispecific antibody. The inventive features center on the bispecific antibody binding structure, including defined CDR/sequence constraints or specified epcoritamab, and a step-up, cycle-dependent dosing regimen in 28-day cycles with continuation criteria tied to response, progression, or unacceptable toxicity.
Subcutaneous administration of a CD3ε×CD20 bispecific antibody with defined CDR sequences
Subcutaneously administering to the subject a bispecific antibody comprising a first binding arm that binds to human CD3ε and a second binding arm that binds to human CD20, wherein the VH and VL regions contain CDR1, CDR2 and CDR3 sequences in specified VH and VL region sequences of SEQ ID NO: 6 and 7 for the CD3ε arm, and SEQ ID NO: 13 and 14 for the CD20 arm.
Step-up priming and intermediate dosing with 28-day cycle full dosing
Administering the bispecific antibody at a full dose ranging from 12–360 mg in 28-day cycles, including administering a priming dose on day 1 of cycle 1 and an intermediate dose on day 8 of cycle 1 before administration of the first full dose on day 15 of cycle 1, with the priming dose and intermediate dose lower than the full dose.
Continuation until CR, PR, stable disease, progressive disease, or unacceptable toxicity
Continuing administration of the full dose at least until the subject exhibits a complete response, a partial response, or stable disease, or until progressive disease develops or unacceptable toxicity occurs.
Cycle-dependent dosing schedule across cycles 1 to 10 and subsequent cycles
Administering the bispecific antibody in 28-day cycles with full doses on days 15 and 22 in cycle 1, days 1, 8, 15, and 22 in cycles 2–3, days 1 and 15 in cycles 4–9, and day 1 in cycle 10 and subsequent cycles.
Bispecific antibody defined by chain amino acid sequences
Subcutaneously administering a bispecific antibody comprising a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively.
Epcoritamab subcutaneous dosing in 28-day cycles
Subcutaneously administering epcoritamab with step-up priming and intermediate dosing, cycle-dependent full-dose scheduling, and continuation until complete response, partial response, stable disease, progressive disease, or unacceptable toxicity.
Across the independent claims, the inventive coverage is directed to treating human CLL using a CD3ε×CD20 bispecific antibody given subcutaneously, with defined antigen-binding arm sequence constraints or specified chain amino acid sequences, together with step-up priming and intermediate dosing in cycle 1 and a detailed cycle-dependent schedule for full-dose administration in 28-day cycles.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of chronic lymphocytic leukemia in a human subject.
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