Combination therapy for treating cancer with an antibody and intravenous administration of a recombinant MVA
Inventors
Hochrein, Hubertus • Lauterbach, Henning • Medina Echeverz, José • Habjan, Matthias
Assignees
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Publication Number
US-11723964-B2
Publication Date
2023-08-15
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 provides a method of inducing both an innate and adaptive immune response in a patient by administering intravenously 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. The method further includes administering an antibody that comprises an Fc domain and is specific to an antigen expressed on the cell membrane of a tumor cell.
The approach uses an Fc-domain tumor-cell membrane-targeting antibody together with an intravenous recombinant MVA encoding tumor-associated antigens and CD40L to enhance both innate and adaptive immunity. The document emphasizes a synergistic interaction between the intravenous MVA and the antibody for inducing tumor-related immune responses, including enhanced NK cell response and enhanced T cell response.
In refinements, the first heterologous tumor-associated antigen is specified as HER2, and the HER2 antigen includes mutation sets affecting HER2 binding and/or HER2 biological functions. The document further includes embodiments in which the recombinant MVA comprises an additional nucleic acid encoding the heterologous tumor-associated antigen Brachyury, with constraints on Brachyury nuclear localization signal (NLS) domain mutations or deletion.
Claims Coverage
The available claim coverage centers on one inventive combination: co-administering an intravenous recombinant MVA encoding a heterologous TAA and CD40L with an Fc-domain tumor-cell membrane-targeting antibody to induce enhanced NK and T cell responses. Dependent coverage further refines the heterologous TAA as HER2 or Brachyury and adds specific mutation or deletion constraints.
Intravenous recombinant MVA encoding a first heterologous TAA and CD40L
Administering intravenously 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-cell membrane antigen-specific antibody
Administering an antibody that comprises an Fc domain and is specific to an antigen expressed on the cell membrane of a tumor cell.
Enhanced NK and T cell responses
Inducing an enhanced Natural Killer (NK) cell response and an enhanced T cell response in the patient.
HER2 as the first heterologous tumor-associated antigen
The method wherein the first nucleic acid encodes a tumor-associated antigen that is HER2.
Trastuzumab-linked HER2 binding-domain mutation set
The method wherein the antibody used in step (b) is trastuzumab and the HER2 antigen includes at least one mutation in the trastuzumab binding domain selected from E580, D582, P594, F595, K615, and Q624 corresponding to the amino acid sequence in SEQ ID NO:13.
HER2 variant constrained by defined mutation categories affecting dimerization, kinase activity, or phosphorylation
The method wherein the HER2 antigen includes at least one of the listed mutations affecting HER2 dimerization, tyrosine kinase activity, or phosphorylation, including mutations selected from D277R, E280K, K753M, Y1023A, and deletion of residues 1139-1248, and other defined substitution groupings.
Addition of Brachyury as a further heterologous tumor-associated antigen
The method wherein the recombinant modified vaccinia virus Ankara (MVA) further contains a third nucleic acid that encodes the heterologous tumor-associated antigen (TAA) Brachyury.
Brachyury NLS-domain mutation or deletion constraint
The method wherein the Brachyury antigen includes one or more mutations in the nuclear localization signal (NLS) domain or has the NLS domain deleted.
The core claim coverage is the paired administration of an intravenous recombinant MVA expressing a heterologous tumor-associated antigen and CD40L with an Fc-domain antibody targeting a tumor cell membrane antigen, to induce enhanced NK and T cell responses. Additional coverage selects HER2, including specific trastuzumab-binding-domain mutation sets and constrained HER2 variant categories, and optionally adds Brachyury with NLS-domain mutation or NLS deletion constraints.
Stated Advantages
Inducing both an innate and adaptive immune response in the patient.
Inducing an enhanced Natural Killer (NK) cell response.
Inducing an enhanced T cell response.
Tailoring the HER2 antigen variant or mutations to an antibody, including trastuzumab-linked binding-domain mutations.
Including Brachyury with constraints on the nuclear localization signal (NLS) domain.
Documented Applications
Cancer immunotherapy pharmaceutical combinations for inducing immune responses in a patient, including enhanced NK activity and enhanced T cell responses.
Therapeutic targeting involving HER2 and/or Brachyury as heterologous tumor-associated antigens in combination with CD40L-encoding recombinant MVA and an Fc-domain antibody specific to a tumor-cell membrane antigen.
A method for inducing both an innate and adaptive immune response in a patient using an intravenous recombinant MVA and an Fc-domain tumor-surface-targeting antibody.
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