Abstract
The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico-chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE-987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader-antibody conjugate by attaching GNE-987 to an anti-CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen-specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.
Keywords:
BRD4; antibodies; antibody-drug conjugate; chimeric protein degrader; drug delivery.
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
MeSH terms
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Animals
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Antibodies, Monoclonal / chemistry*
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Antibodies, Monoclonal / immunology
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Carriers / chemistry
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Female
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Half-Life
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Heterocyclic Compounds, 4 or More Rings / chemistry*
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Humans
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Immunoconjugates / chemistry*
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Immunoconjugates / pharmacology
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Immunoconjugates / therapeutic use
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Lectins, C-Type / immunology
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Leukemia, Myeloid, Acute / drug therapy
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Leukemia, Myeloid, Acute / pathology
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Mice
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Mice, SCID
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Protein Binding
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Proteolysis / drug effects
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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Receptors, Mitogen / immunology
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Surface Plasmon Resonance
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism*
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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BRD4 protein, human
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CLEC12A protein, human
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Cell Cycle Proteins
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Drug Carriers
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Heterocyclic Compounds, 4 or More Rings
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Immunoconjugates
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Lectins, C-Type
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Proto-Oncogene Proteins c-myc
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Receptors, Mitogen
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Transcription Factors
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human