Oncolytic virus adjunct therapy with agents that increase virus infectivity
Inventors
Szalay, Aladar A. • Cappello, Joseph • Chen, Nanhai G. • Minev, Boris
Assignees
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Publication Number
US-10238700-B2
Publication Date
2019-03-26
Expiration Date
Abstract
Provided are adjunct therapies for use in combinations and compositions with an oncolytic virus, such as a vaccinia virus. The adjunct therapies include co-administration and co-formulation of a complement inhibitor and/or a lipid emulsion composition with the oncolytic virus. Also provided herein are therapeutic methods using the adjunct therapies for treatment of disease and conditions employing an oncolytic therapeutic virus, such as for the treatment of hyperproliferative diseases or conditions including tumors or cancers.
Core Innovation
The invention relates to adjunct therapy that combines an oncolytic vaccinia virus with an anti-complement component 5 (C5) antibody targeting the C5 alpha chain. The approach is described for inhibiting complement activation and reducing anaphylatoxic C5a and C5b-9 membrane attack complex (MAC), thereby increasing infectivity of the oncolytic virus in a human body fluid. The antibody is selected from eculizumab, pexelizumab, TSA12/22, and MB12/122, including variants that bind the C5 alpha chain.
The disclosed mechanism specifies that certain eculizumab/pexelizumab variants specifically bind the alpha chain of human complement component C5 and inhibit complement activation, inhibit binding of purified human complement component C5 to human complement component C3 or C4, and do not specifically bind free C5a. Other variants, including TSA12/22 and MB12/122, specifically bind a region corresponding to residues 727-744 of SEQ ID NO: 53 of the human C5 component or a region having at least 80% homology thereto, and inhibit conversion of the C5 alpha chain to C5a and C5b.
The invention also covers pharmaceutical compositions and combinations that include a vaccinia oncolytic virus and an anti-C5 antibody in an amount effective for inhibiting complement activation. In related embodiments, the oncolytic virus includes LIVP viruses and named vaccinia strains, including GLV-1h68 or a derivative, and additional embodiments include a lipid emulsion component comprising biocompatible fatty acids, fatty acid derivatives, or related lipid emulsion components such as Intralipid®.
Claims Coverage
The document includes three independent claim groupings covering a method, a composition, and a combination. Across the independent claims, three principal inventive feature groupings are the vaccinia oncolytic virus, the anti-C5 alpha-chain antibody selection and C5-functional binding/inhibition characteristics, and the amount-effective structure for inhibiting complement activation, with optional lipid-emulsion related refinements in dependent claims.
Increasing infectivity with vaccinia virus and anti-C5 alpha-chain antibody
Administering an oncolytic virus and an anti-C5 antibody to a subject, wherein the oncolytic virus is a vaccinia virus; wherein the virus and antibody are administered separately, in the same composition, sequentially or intermittently; wherein the antibody binds to the alpha chain of complement C5 and is selected from among eculizumab, pexelizumab, TSA12/22 and MB12/122, and variants thereof that bind to the C5 alpha chain; and wherein the anti-C5 antibody is administered in an amount effective for inhibiting complement activation in a subject.
Anti-C5 alpha-chain antibody variants with defined binding and complement inhibition characteristics
Using an anti-complement component 5 (C5) antibody that binds to the C5 alpha chain and is selected from among eculizumab, pexelizumab, TSA12/22 and MB12/122, and variants thereof that bind to the C5 alpha chain, wherein eculizumab/pexelizumab variants specifically bind to the alpha chain of human complement component C5 and inhibit complement activation in a human body fluid, inhibit binding of purified human complement component C5 to human complement component C3 or human complement component C4, and do not specifically bind free C5a; and wherein TSA12/22 and MB12/122 variants recognize a region corresponding to residues 727-744 of SEQ ID NO: 53 of the C5 component of human complement or a region having at least 80% homology thereto and inhibit conversion of the C5 alpha chain to C5a and C5b.
Pharmaceutical composition combining vaccinia oncolytic virus with anti-C5 alpha-chain antibody
Providing a composition comprising, in a pharmaceutically acceptable carrier, an oncolytic virus wherein the oncolytic virus is a vaccinia virus, and an anti-complement component 5 (C5) antibody that binds to the C5 alpha chain and is selected from among eculizumab, pexelizumab, TSA12/22 and MB12/122, and variants thereof that bind to the C5 alpha chain, wherein the antibody is in an amount effective for inhibiting complement activation in a subject and exhibits the defined binding and inhibition characteristics.
Two-composition combination for inhibiting complement activation with vaccinia virus and anti-C5 alpha-chain antibody
Providing a combination comprising a first composition comprising an oncolytic virus wherein the oncolytic virus is a vaccinia virus, and a second composition comprising an anti-C5 antibody that binds to the C5 alpha chain and is in an amount effective for inhibiting complement activation in a subject, wherein the anti-C5 antibody is selected from among eculizumab, pexelizumab, TSA12/22 and MB12/122, and variants thereof that bind to the C5 alpha chain and wherein the antibody exhibits the defined eculizumab/pexelizumab or TSA12/22/MB12/122 binding and inhibition characteristics.
Across the independent claims, coverage centers on using a vaccinia oncolytic virus together with an anti-C5 antibody that binds the C5 alpha chain, where the antibody’s binding specificity and complement inhibition behavior are explicitly defined. The claims further require an amount effective to inhibit complement activation in a subject, implemented either as a method with separate administration, as a single pharmaceutical composition, or as a combination of first and second compositions.
Stated Advantages
Increases infectivity of an oncolytic virus by inhibiting complement activation.
Inhibits complement activation to reduce complement-mediated effects associated with C5a and C5b-9 (MAC).
Reduces complement-mediated serum inactivation of GLV-1h68.
Increases virus association with human blood cells.
Reduces sensitivity of the oncolytic virus to serum inactivation.
Documented Applications
Adjunct therapy combining an oncolytic vaccinia virus with anti-C5 antibodies targeting the C5 alpha chain to inhibit complement activation and preserve or increase virus infectivity in blood or serum contexts.
Use of eculizumab to reduce complement-mediated serum inactivation of GLV-1h68 and increase virus association with human blood cells.
Use of Intralipid® pretreatment to reduce sensitivity of the oncolytic virus to serum inactivation.
Adjunct cancer therapy using oncolytic vaccinia viruses in tumors or hyperproliferative diseases, where complement-mediated clearance can reduce virus infectivity and the method or combination is used to increase infectivity by inhibiting complement activation.
Use of compositions and combinations that pair oncolytic vaccinia viruses with anti-C5 alpha-chain antibodies as pharmaceutically acceptable carrier formulations and adjunct combinations for administration to a subject.
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