Combination therapy for treating cancer with an intravenous administration of a recombinant MVA and an antibody
Inventors
Hochrein, Hubertus • Lauterbach, Henning • Medina Echeverz, José • Habjan, Matthias
Assignees
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Publication Number
US-11273211-B2
Publication Date
2022-03-15
Expiration Date
Abstract
The invention relates to a pharmaceutical combination and related methods for reducing tumor volume and/or increasing the survival of a cancer patient. The combination comprises an intravenous administration of a recombinant MVA encoding a tumor-associated antigen and an administration of an antibody to a cancer patient.
Core Innovation
The invention relates to a pharmaceutical composition for cancer immunotherapy that includes a recombinant modified vaccinia virus Ankara (MVA) and an antibody. The recombinant MVA comprises a first nucleic acid encoding a first heterologous tumor-associated antigen (TAA) and a second nucleic acid encoding CD40L, and the antibody comprises an Fc domain and is specific to an antigen expressed on the cell membrane of a tumor cell.
Administration of the antibody and intravenous administration of the recombinant MVA to a cancer patient induces enhanced Natural Killer (NK) cell response and enhanced T cell response compared to treatment with the antibody alone or non-intravenous administration of the recombinant MVA alone. The composition is described as potentiating immune responses and associated with enhanced innate and adaptive immune responses.
In embodiments, the first heterologous TAA is HER2 and/or Brachyury. The document further describes HER2 variants with specified binding-domain mutations to avoid binding by trastuzumab and/or pertuzumab, and Brachyury embodiments with mutations in the nuclear localization signal (NLS) domain and/or deletion of the NLS domain.
Claims Coverage
The independent claim covers a pharmaceutical composition combining an intravenously administered recombinant MVA engineered to encode a heterologous TAA and CD40L and an Fc-domain antibody specific to a tumor-cell membrane antigen, where the combination induces enhanced NK-cell response and enhanced T-cell response versus antibody alone or non-intravenous MVA alone. Three inventive features are central, with dependent claims refining the specific TAA and antigen sequence variants.
Engineered recombinant MVA with heterologous TAA and CD40L
A recombinant modified vaccinia virus Ankara (MVA) comprising a first nucleic acid encoding a first heterologous tumor-associated antigen (TAA) and a second nucleic acid encoding CD40L.
Fc-domain tumor-membrane-specific antibody
An antibody that comprises an Fc domain and is specific to an antigen expressed on the cell membrane of a tumor cell.
Intravenous MVA combined with antibody to enhance NK and T cell responses
Administration of the antibody and intravenous administration of the recombinant MVA to a cancer patient induces an enhanced Natural Killer (NK) cell response and an enhanced T cell response compared to treatment with the antibody alone or a non-intravenous administration of the recombinant MVA alone.
HER2 as the heterologous tumor-associated antigen
The pharmaceutical composition wherein the first heterologous tumor-associated antigen is HER2.
HER2 variant with trastuzumab-binding-domain mutations
The pharmaceutical composition wherein the antibody comprises trastuzumab and the HER2 antigen includes at least one specified mutation in the trastuzumab binding domain corresponding to amino acid positions E580, D582, P594, F595, K615, and Q624 as in SEQ ID NO:13.
HER2 variant with pertuzumab-binding-domain mutations
The pharmaceutical composition wherein the antibody comprises pertuzumab and the HER2 antigen includes at least one specified mutation in the pertuzumab binding domain corresponding to the amino acid sequence of SEQ ID NO:13, including H267, Y274, F279, V308, S310, L317, H318, K333, and P337.
HER2 mutations affecting extracellular dimerization, tyrosine kinase activity, and phosphorylation
The pharmaceutical composition wherein the HER2 antigen includes specific mutations affecting HER2 extracellular dimerization, tyrosine kinase activity, and/or phosphorylation, or includes a deletion of residues 1139-1248.
Brachyury variant with nuclear localization signal domain mutations and/or deletion
A pharmaceutical combination wherein the Brachyury antigen has mutations in the nuclear localization signal (NLS) domain and/or lacks the NLS domain.
The claim coverage centers on an intravenous regimen combining an Fc-domain tumor-membrane-specific antibody with an engineered recombinant MVA that encodes a heterologous TAA and CD40L, with the comparative outcome of enhanced NK and enhanced T cell responses. Dependent claims further define HER2 and Brachyury embodiments and constrain the encoded antigen sequences using specified mutation categories and NLS-domain modifications.
Stated Advantages
Induces an enhanced Natural Killer (NK) cell response compared to administration with the Fc-domain antibody alone or non-intravenous administration of the recombinant MVA alone.
Induces an enhanced T cell response compared to administration with the Fc-domain antibody alone or non-intravenous administration of the recombinant MVA alone.
Associated with enhanced NK activity, ADCC, and increased CD8/CD4 T-cell responses, as well as improved tumor control and survival in the illustrated examples.
Documented Applications
Cancer immunotherapy using a pharmaceutical composition that combines an Fc-domain antibody specific to a tumor-cell membrane antigen with an intravenously administered recombinant MVA encoding a heterologous tumor-associated antigen and CD40L.
Uses the pharmaceutical composition to treat a cancer patient by inducing enhanced Natural Killer (NK) cell response and enhanced T cell response.
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