Oncolytic virus for expression of immune checkpoint modulators
Inventors
Silvestre, Nathalie • Geist, Michel • Rittner, Karola • Marchand, Jean-Baptiste • Thioudellet, Christine
Assignees
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Publication Number
US-10555981-B2
Publication Date
2020-02-11
Expiration Date
Abstract
The present invention provides an oncolytic virus comprising nucleotide sequence(s) encoding one or more immune checkpoint modulator(s). It also concerns a pharmaceutical composition comprising effective amount of said oncolytic virus and, eventually, a pharmaceutically acceptable vehicle and its use for treating proliferative diseases such as cancers.
Core Innovation
The invention describes a method for treating a proliferative disease by administering an oncolytic virus comprising inserted nucleic acid encoding one or more immune checkpoint modulators. The oncolytic virus is a vaccinia virus engineered to be defective for ribonucleotide reductase (RR) activity by inactivating mutations in only the viral 14L gene and defective for thymidine kinase (TK) activity by inactivating mutations in the J2R viral gene. The inserted immune-checkpoint encoding nucleic acid is carried in the viral genome and is intended to modulate immune checkpoint activity in the treated subject.
In the described embodiments, the one or more immune checkpoint modulators is an antibody that specifically binds to PD-1. The method includes administering either the engineered oncolytic virus or a pharmaceutical composition comprising an effective amount of the oncolytic virus, together with a pharmaceutical acceptable vehicle. The immune checkpoint modulator antibody formats include antibodies such as mAb, Fab, and scFv, and PD-1 binding with named examples including mPD-1/J43 formats.
The documented approach further includes vaccinia vectors that express immune checkpoint modulators and optionally additional therapeutic genes, including suicide genes and immunostimulatory proteins, in the context of cancer treatment. The provided content states that the engineered TK−RR− vaccinia expressing anti-mPD-1 J43 antibody formats preserves oncolytic activity while enabling PD-1 binding and blocking, and shows tumor-associated antibody accumulation relative to subcutaneous tissue following intratumoral dosing in a murine model.
Claims Coverage
The only independent claim provided covers a treating method requiring an oncolytic vaccinia virus genome with specific RR and TK inactivating mutations and inserted immune checkpoint modulator(s) where the modulator is an antibody specifically binding to PD-1, administered as a virus or within a pharmaceutical composition. The independent claim therefore frames a single core inventive concept and relies on dependent claims to refine disease scope, antibody options, formulation and dose ranges, administration schedules, and optional gene embodiments.
Oncolytic vaccinia with 14L and J2R defects for immune checkpoint modulation
Administering an oncolytic virus comprising inserted in its genome a nucleic acid molecule encoding one or more immune checkpoint modulator(s), wherein said virus is a vaccinia virus defective for ribonucleotide reductase (RR) activity resulting from inactivating mutations in only the viral 14L gene and defective for thymidine kinase (TK) resulting from inactivating mutations in the J2R viral gene.
PD-1 binding antibody as immune checkpoint modulator
The one or more immune checkpoint modulator(s) is an antibody that specifically binds to PD-1.
Therapeutic administration via virus or effective-dose pharmaceutical composition
Administering a pharmaceutical composition comprising an effective amount of said oncolytic virus wherein said virus is a vaccinia virus defective for ribonucleotide reductase (RR) activity resulting from inactivating mutations in only the viral 14L gene and defective for thymidine kinase (TK) resulting from inactivating mutations in the J2R viral gene, and wherein said one or more immune checkpoint modulator(s) is an antibody that specifically binds to PD-1 and a pharmaceutical acceptable vehicle.
Across the independent claim, protection is directed to using a specifically engineered TK−RR− vaccinia virus that carries nucleic acid encoding a PD-1-binding antibody immune checkpoint modulator, administered either as the oncolytic virus or as a pharmaceutical composition containing an effective amount and a pharmaceutical acceptable vehicle.
Stated Advantages
Preserves oncolytic activity while enabling PD-1 binding and blocking.
Shows tumor-associated antibody accumulation relative to subcutaneous tissue following intratumoral dosing in a murine model.
Documented Applications
Treating proliferative disease.
Cancer treatment.
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