Anti-TNF-alpha-antibodies and functional fragments thereof
Inventors
Gunde, Tea • Meyer, Sebastian • FURRER, Esther Maria
Assignees
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Publication Number
US-12043663-B2
Publication Date
2024-07-23
Expiration Date
Abstract
The present invention relates to antibody molecules and functional fragments thereof, capable of binding to tumor necrosis factor alpha (TNFα), to processes for their production, and to their therapeutic uses.
Core Innovation
The invention relates to anti-human tumor necrosis factor alpha (TNFα) antibody molecules and functional fragments capable of binding human TNFα. The antibodies are defined by specific variable-domain CDR amino-acid sequences for the V_L and V_H domains, with particular CDR1, CDR2, and CDR3 regions identified by SEQ ID NOs. The disclosed formats include humanized scFv, diabody, and IgG, together with functional fragments.
The disclosed TNFα-binding antibodies are characterized by high TNFα affinity, strong TNFα neutralization potency in an L929 TNFα-induced apoptosis assay, and inhibition of LPS-induced cytokine secretion, including IL-1β and TNFα. The document further describes target-blocking effects on TNFRI and TNFRII and assessment of TNFα complex formation and stoichiometry.
Cross-reactivity and selectivity are described in terms of interaction with Cynomolgus/Rhesus TNFα, as well as TNFβ selectivity, including statements that no significant TNFβ binding occurs and that high TNFβ/TNFα IC50 selectivity is achieved. Variable-domain stability is also described, including melting temperature (Tm) by DSF and low monomer loss after storage and freeze-thaw.
Claims Coverage
The independent claim is directed to an antibody or functional fragment capable of binding human TNFα, selected from three specified CDR sequence-defined variants. The inventiveness centers on the specified V_L and V_H CDR amino-acid sequence combinations via listed SEQ ID NOs.
CDR-defined human TNFα-binding antibody variants
An antibody or functional fragment capable of binding human tumor necrosis factor alpha (TNFα), wherein the antibody is selected from three variants defined by V_L and V_H domain CDR1/2/3 amino-acid sequences shown in the listed SEQ ID NOs.
Overall claim coverage is anchored on three CDR-sequence-defined antibody or functional fragment variants that bind human TNFα, with dependent claim elements refining format, quantitative binding and potency benchmarks, and downstream forms including nucleic acids, vectors/cells, pharmaceutical compositions, and treatment/prevention methods for TNFα-related disorders.
Stated Advantages
High TNFα affinity.
Greater potency in inhibiting TNFα-induced apoptosis than infliximab as determined by an L929 assay.
Enhanced inhibition of LPS-induced cytokine secretion, including IL-1β and TNFα.
Substantial cross-reactivity to Cynomolgus/Rhesus TNFα within desired fold ranges.
TNFβ selectivity with no significant TNFβ binding and high TNFβ/TNFα IC50 selectivity.
Variable-domain stability with high Tm by DSF and low monomer loss after storage/free-thaw.
Documented Applications
Treatment or prevention of inflammatory bowel disease, including Crohn’s disease, ulcerative colitis, and microscopic colitis, using an orally administered pharmaceutical composition comprising the antibody or functional fragment.
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