Egfr antibody conjugates
OwnerIlia Alexandre Tikhomirovinventor
Life of this patent
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Abstract
A maytansinoid is covalently linked through a non-cleavable linker to an EGFR antibody that is a full EGFR antagonist, such as cetuximab or panitumumab. The result is an anti-cancer agent having cytotoxicity that is potentiated in cancer cells but not normal cells. This benefit is not seen with EGFR antibodies that are partial antagonists, or with toxins that are not processed by lysosomes.
Claims21
A method useful to potentiate the cytotoxicity of an EGFR antibody or an EGFR-binding fragment thereof on EGFR+ disease cells without potentiating the cytotoxicity thereof on normal EGFR+ cells, the method comprising:
- (i) selecting, for conjugation, an EGFR antibody that is a full EGFR antagonist and competes with cetuximab for binding to EGFR, or an EGFR-binding fragment of said antibody;
- (ii) selecting, for delivery by the EGFR antibody or fragment thereof, an anti-microtubule toxin;
- (iii) selecting, for coupling the selected EGFR antibody and the anti-microtubule toxin, a linker;
- and
- producing an immunoconjugate that incorporates the linker between the antibody and the toxin, thereby providing an immunoconjugate having a cytotoxicity that is potentiated against EGFR+ disease cells and essentially not potentiated against EGFR+ keratinocyte cells.
An immunoconjugate comprising (i) a full antagonist EGFR antibody that binds to an EGFR epitope to which cetuximab binds, or an EGFR binding fragment of said antibody or single chain polypeptide based on said antibody, and (ii) an anti-microtubule toxin conjugated therewith, the immunoconjugate having a cytotoxic effect relative to a naked form of said antibody that is (1) potentiated with respect to EGFR+ cancer cells, and (2) substantially unaltered with respect to EGFR+ keratinocytes, wherein the antibody and toxin are conjugated by a linker.
A method for producing an anti-cancer composition, comprising the step of combining a pharmaceutically acceptable carrier, and an EGFR antibody that is conjugated to an anti-microtubule toxin to form an immunoconjugate, the immunoconjugate having an effect on cancer cells that is potentiated and an effect on keratinocytes that is essentially not potentiated, relative to the effects of the naked antibody on such cells.
(canceled)
A method for potentiating the effect of a full antagonist EGFR antibody on EGFR+ disease cells without potentiating the effect thereof on normal EGFR+ cells, comprising linking the antibody to an anti-microtubule toxin by a non-cleavable linker.
In a method for treating a subject presenting with a tumor that responds to treatment with a full antagonist EGFR antibody, wherein treatment therewith elicits an EGFR antibody-mediated adverse response by keratinocytes, the improvement comprising:
- treating the subject with the full antagonist EGFR antibody in a form conjugated with an anti-microtubule toxin, whereby the tumor response to treatment with conjugated antibody is enhanced essentially without enhancing the adverse keratinocyte response to treatment, relative to treatment with naked antibody alone.
Dependencies are inferred from the claim text.