Compositions and methods to enhance the immune system
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Publication Number
US-9790275-B2
Publication Date
2017-10-17
Expiration Date
Abstract
The invention relates to the field of molecular medicine. In particular, it relates to compositions and methods to enhance the clearance of aberrant cells, e.g. cancer cells or virus-infected cells, by the host's immune system. Provided is a composition comprising (i) a therapeutic compound that can trigger a host's immune effector cells against an aberrant cell, such as a therapeutic antibody, and (ii) at least one agent capable of reducing or preventing inhibitory signal transduction initiated via SIRPalpha.
Core Innovation
The invention relates to enhancing in vivo efficacy of a therapeutic antibody to induce cancer cell destruction by antibody-dependent cellular cytotoxicity (ADCC) in a human subject receiving anti-cancer treatment with a therapeutic antibody comprising a human or non-human primate IgG Fc portion. The approach administers an agent capable of reducing or preventing inhibitory signal transduction initiated via SIRPα, in an amount sufficient to increase ADCC such that the in vivo efficacy of the therapeutic antibody is enhanced.
The agent that reduces or prevents inhibitory signal transduction initiated via SIRPα is an anti-SIRPα antibody or an antibody fragment thereof, including Fab, F(ab’)2, or ScFv fragments. The patent states that CD47 on aberrant cells engages SIRPα on myeloid cells to suppress antibody-mediated killing, and that blocking this SIRPα inhibitory signaling potentiates ADCC and related immune effector functions.
The document extends the concept to treating cancer using therapeutic antibodies selected from rituximab, trastuzumab, alemtuzumab, bevacizumab, cetuximab, and panitumumab, with administration of the anti-SIRPα agent prior to, simultaneously with, or after the therapeutic antibody. It also describes a related application framework involving poxviruses expressing viral CD47 (vCD47) to suppress killing/phagocytosis, with enhancement proposed for resistance and vaccination effectiveness against poxviral pathogens.
Claims Coverage
The document includes two independent claims. Across these independent claims, there are inventive features covering enhancing in vivo ADCC efficacy of an anti-cancer therapeutic IgG Fc antibody and treating cancer by administering an anti-SIRPα inhibitory-signaling agent in relation to the therapeutic antibody dosing schedule.
Enhancing in vivo ADCC efficacy by blocking SIRPα inhibitory signaling
A method of enhancing in vivo efficacy of a therapeutic antibody to induce cancer cell destruction by antibody-dependent cellular cytotoxicity (ADCC) in a human subject receiving anti-cancer treatment with a therapeutic antibody comprising a human or non-human primate IgG Fc portion, wherein the therapeutic antibody induces ADCC, comprising administering an agent capable of reducing or preventing inhibitory signal transduction initiated via SIRPα, wherein the agent is an amount sufficient to increase ADCC such that the in vivo efficacy of the therapeutic antibody is enhanced.
Anti-SIRPα agent as Fab/F(ab’)2/ScFv to reduce or prevent SIRPα inhibitory signal transduction
The method wherein the agent capable of reducing or preventing inhibitory signal transduction initiated via SIRPα is an anti-SIRPα antibody or a Fab fragment thereof, a F(ab’)2 fragment thereof, or a ScFv fragment thereof.
Timing of anti-SIRPα agent relative to therapeutic IgG Fc antibody administration
The method wherein the anti-SIRPα agent is administered to the subject prior to, simultaneously, or after the administration of the therapeutic antibody.
Treating cancer with selected therapeutic antibodies plus an anti-SIRPα agent
A method of treating cancer in a subject receiving anti-cancer treatment with a therapeutic antibody selected from rituximab, trastuzumab, alemtuzumab, bevacizumab, cetuximab, and panitumumab, comprising administering to the human subject prior to, simultaneously, or after the administration of the therapeutic antibody an anti-SIRPα antibody, a Fab fragment, a F(ab’)2 fragment, or a ScFv fragment.
The independent claims focus on potentiating cancer cell destruction mediated by ADCC by administering an anti-SIRPα inhibitory-signaling agent in relation to treatment with a therapeutic IgG Fc antibody, including specific listed therapeutic antibodies, with dosing timing prior to, simultaneously, or after the therapeutic antibody.
Stated Advantages
Increases ADCC such that the in vivo efficacy of the therapeutic antibody to induce cancer cell destruction by ADCC is enhanced.
Documented Applications
Enhancing killing/phagocytosis and cancer treatment by administering an agent that reduces or prevents inhibitory signal transduction initiated via SIRPα in a subject receiving anti-cancer treatment with a therapeutic antibody.
Viral infection application framework involving poxviruses expressing viral CD47 (vCD47) to suppress killing/phagocytosis, with enhancement proposed for resistance and vaccination effectiveness against poxviral pathogens.
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