Methods for the treatment of disease using immunoglobulins having fc regions with altered affinities for FcgammaRactivating and FegammaRinhibiting
Inventors
Stavenhagen, Jeffrey B. • Koenig, Scott
Assignees
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Publication Number
US-11787871-B2
Publication Date
2023-10-17
Expiration Date
Abstract
The present invention relates to methods of treating or preventing cancer and other diseases using molecules, particularly polypeptides, more particularly immunoglobulins (e.g., antibodies), comprising a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, which variant Fc region binds an FcγR that activates a cellular effector (“FcγRActivating,” such as FcγRIIA or FcγRIIIA) and an FcγR that inhibits a cellular effector (“FcγRInhibiting,” such as FcγRIIA) with an altered Ratio of Affinities relative to the respective binding affinities of such FcγR for the Fc region of the wild-type immunoglobulin. The methods of the invention are particularly useful in preventing, treating, or ameliorating one or more symptoms associated with a disease, disorder, or infection where either an enhanced efficacy of effector cell function mediated by FcγR is desired (e.g., cancer, infectious disease) or an inhibited effector cell response mediated by FcγR is desired (e.g., inflammation, autoimmune disease).
Core Innovation
The invention provides an isolated nucleic acid molecule encoding an antibody that comprises an antigen binding region and a variant Fc region. The variant Fc region is a variant of a human IgG Fc region and comprises the amino acid modifications F243L, R292P and Y300L, with positions numbered according to the EU index as in Kabat. The disclosed antibody and Fc-variant formats maintain an antigen binding region while defining the variant Fc by these substitutions.
The document frames the Fc variant concept in terms of FcγR biology and signaling, distinguishing activating FcγRs (FcγRIIA and FcγRIIIA) from the inhibitory FcγR (FcγRIIB). It describes altered interaction profiles with FcγRIIB and FcγRIIIA/FcγRIIA and links this FcγR binding modulation to downstream effector functions, including ADCC and related effector-associated phenotypes.
The core approach includes using the defined variant Fc region in antibody therapeutics for effector-function modulation. The described embodiments link the variant Fc to enhanced effector functions and to dampening effector responses, and also describe vaccine therapy concepts in which antigen is coated with FcγRIIIA-enhanced variant antibodies and tolerance induction via FcγRIIB-enhancing variant antibodies.
Claims Coverage
The independent claims are directed to two inventive features: an isolated nucleic acid encoding an antibody with a human IgG Fc variant containing F243L, R292P and Y300L, and a recombinant method for producing such an antibody by culturing a host cell and recovering the antibody. The claims center on the defined Fc substitutions, the antigen binding region, and recombinant production and recovery.
Variant Fc region with F243L, R292P and Y300L substitutions
An isolated nucleic acid molecule encoding an antibody comprising an antigen binding region and a variant Fc region, wherein the variant Fc region is a variant of a human IgG Fc region and comprises the amino acid modifications relative to a wild-type Fc region: F243L, R292P and Y300L, wherein the positions are numbered according to the EU index as in Kabat.
Recombinant production using host cell culturing and recovering an antibody having the specified variant Fc
A method for recombinantly producing an antibody comprising culturing in a medium a host cell comprising a nucleic acid molecule encoding an antibody under conditions suitable for expression, wherein said antibody comprises an antigen binding region and a variant Fc region comprising F243L, R292P and Y300L, and recovering said antibody from said medium.
The independent claims focus on the same defining Fc engineering concept: a human IgG Fc variant with F243L, R292P and Y300L substitutions as numbered according to the EU/Kabat index. One claim covers the nucleic acid encoding the engineered antibody, and the other covers recombinant production by culturing a host cell and recovering the expressed antibody.
Stated Advantages
Increased activating FcγRIIIA and FcγRIIA binding.
Decreased and/or abolished inhibitory FcγRIIB binding.
Enhanced ADCC.
Altered C1q binding and CDC/effector functions.
Enhance effector functions (e.g., ADCC/ADCP/CDC) for cancer and infectious diseases.
Dampen effector responses for autoimmune/inflammatory disorders.
Documented Applications
Engineered antibodies with variant Fc regions for altered effector functions including ADCC, complement-associated activity (C1q binding and CDC/effector functions), and related phenotypes described in the document.
Engineered immunoglobulin formats with variant Fc regions as described in the document.
Therapeutics for cancer, including targeting cancer antigens (e.g., Her2/neu and CD20, and other named cancer antigens).
Therapeutics for infectious diseases.
Therapeutics for autoimmune/inflammatory disorders.
Vaccine therapy concepts in which antigen is coated with FcγRIIIA-enhanced variant antibodies.
Tolerance induction via FcγRIIB-enhancing variant antibodies.
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