Engineered polypeptides and uses thereof
Inventors
Viswanathan, Karthik • Ramakrishnan, Boopathy • Booth, Brian • Narayan, Kristin • Wollacott, Andrew M.
Assignees
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Publication Number
US-11858980-B2
Publication Date
2024-01-02
Expiration Date
Abstract
Polypeptides, such as antibody molecules and fusion proteins, comprising an Fc region, are disclosed. The polypeptides can be used to treat, prevent, and/or diagnose disorders.
Core Innovation
The disclosure describes engineered polypeptides comprising Fc-region CH2 and CH3 domains, including Fc-containing antibody molecules and Fc-fusion proteins, that are designed for improved pharmacokinetics and function. The core engineering approach introduces Fc-region mutations intended to enhance neonatal Fc receptor (FcRn) binding at acidic pH while minimizing FcRn binding at physiological pH. This pH-specific engagement is used to extend in vivo circulating half-life compared with an otherwise identical reference polypeptide that does not include the Fc CH2/CH3 mutations.
The engineered Fc polypeptides are further described in terms of retention or modulation of Fc effector functions mediated through Fcγ receptors and complement components, including C1q/CDC, and functional activities including ADCC/ADCP/ADIN via TRIM21. The disclosure also addresses developability attributes such as stability, solubility, aggregation, and expression, together with measurement frameworks for FcRn binding, thermal stability, aggregation, effector binding and activities, and in vivo half-life.
The invention relates to a polypeptide comprising the CH2 and CH3 domains of an Fc region, where the CH2 and CH3 domains comprise the mutations Q311V and A378V and additionally one, two, or three mutations selected from T256D, N286D, and T307R or T307Q, according to EU numbering. The polypeptide is defined by the specific mutation combination(s) introduced into the Fc CH2 and CH3 domains and is described as exhibiting an increased half-life in vivo compared to an otherwise identical reference polypeptide.
Claims Coverage
The independent claim coverage centers on defined Fc CH2/CH3 mutation sets that yield increased in vivo half-life relative to an otherwise identical reference polypeptide lacking the CH2/CH3 mutations. Across the provided claims content, two inventive feature sets are present: the mutation-defined Fc polypeptide and the functional requirement of increased in vivo half-life.
Fc ch2 and ch3 mutations for increased in vivo half-life
A polypeptide comprising the CH2 and CH3 domains of an Fc region, wherein the CH2 and CH3 domains comprise the mutations Q311V and A378V and one, two, or three mutations selected from T256D, N286D, and T307R or T307Q, wherein the polypeptide has an increased half-life in vivo compared to an otherwise identical reference polypeptide that does not comprise the mutations of the CH2 and CH3 domains.
Engineered fc ch2/ch3 polypeptide with defined mutations
A polypeptide comprising the CH2 and CH3 domains of an Fc region, wherein the CH2 and CH3 domains comprise the mutations Q311V and A378V, and one, two, or three of the mutations selected from T256D, N286D, and T307R or T307Q, according to EU numbering.
Overall claim coverage centers on Fc CH2/CH3 engineering using Q311V and A378V with additional selected mutations from T256D, N286D, and T307R or T307Q, together with the key functional requirement of increased in vivo half-life compared with an otherwise identical reference lacking those CH2/CH3 mutations.
Stated Advantages
Increased half-life in vivo compared to an otherwise identical reference polypeptide that does not comprise the mutations of the CH2 and CH3 domains.
Increased half-life in vivo compared to an otherwise identical reference polypeptide without the specified CH2/CH3 mutations.
Documented Applications
Fc-containing antibody molecules.
Fc-fusion proteins.
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