Compositions and methods to enhance the immune system
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Publication Number
US-9352037-B2
Publication Date
2016-05-31
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 CD47 on aberrant cells engaging SIRPα on myeloid immune effector cells to trigger inhibitory signaling that suppresses antibody-dependent killing and/or phagocytosis (ADCC/ADCP). The inhibitory pathway involves SIRPα-initiated inhibitory signal transduction, which reduces the ability of immune effector cells to mediate therapeutic antibody activity against aberrant cells.
To overcome this suppression, the invention combines an ADCC-triggering therapeutic antibody with an inhibitory agent capable of reducing or preventing inhibitory signal transduction initiated via SIRPα. The inhibitory agent is an anti-CD47 antibody or an anti-SIRPα antibody, including antibody fragments such as Fab, F(ab’)2, or scFv, which antagonize the CD47–SIRPα interaction.
The description further provides supporting evidence that antagonizing CD47–SIRPα enhances ADCP in vitro and enhances in vivo tumor cell killing. It reports improved response in SIRPα signaling-deficient mice and enhanced monocyte-mediated ADCC of Jurkat cells, including increased Rituximab-mediated killing of Raji cells, and extends the approach to viral infections including poxviruses with viral CD47 (vCD47).
Claims Coverage
The patent includes two independent claims that both focus on combining an ADCC-inducing therapeutic antibody with inhibition of SIRPα-initiated signaling to enhance killing of aberrant cells; the claims cover both a composition and a method, with two inventive features centered on an ADCC-triggering therapeutic antibody and an anti-CD47 or anti-SIRPα inhibitory agent.
Combined ADCC-triggering therapeutic antibody and SIRPα inhibitory agent composition
A composition comprising a therapeutic antibody comprising a human or non-human primate IgG Fc portion that induces ADCC and is selected from rituximab, herceptin, trastuzumab, alemtuzumab, bevacizumab, cetuximab and panitumumab, together with at least one agent capable of reducing or preventing inhibitory signal transduction initiated via SIRPα, wherein the agent is an anti-CD47 antibody or an anti-SIRPα antibody or a Fab fragment, a F(ab’)2 fragment or a scFv fragment thereof.
Enhancing in vivo ADCC efficacy by administering a SIRPα inhibitory agent
A method of enhancing in vivo efficacy of a therapeutic antibody to induce cancer cell destruction by ADCC in a 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, by administering prior to, simultaneously or after the therapeutic antibody 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 is enhanced, wherein the agent is an anti-CD47 antibody or an anti-SIRPα antibody or a Fab fragment, a F(ab’)2 fragment or a scFv fragment thereof.
Across both independent claims, the inventive coverage centers on pairing an ADCC-inducing therapeutic IgG Fc antibody with an inhibitory agent that reduces or prevents SIRPα-initiated inhibitory signal transduction via the CD47–SIRPα interaction, using anti-CD47 or anti-SIRPα antibodies or defined fragments, as either a composition or an administration method to enhance in vivo ADCC-driven cancer cell destruction.
Stated Advantages
Increases ADCC such that the in vivo efficacy of the therapeutic antibody to induce cancer cell destruction by ADCC is enhanced.
Antagonizing CD47–SIRPα is reported to enhance in vitro ADCP.
Antagonizing CD47–SIRPα is reported to enhance in vivo tumor cell killing.
Documented Applications
Use in anti-cancer treatment involving ADCC-triggering therapeutic antibodies combined with antagonism of SIRPα-initiated inhibitory signal transduction via CD47–SIRPα.
Extension to viral infections, including poxviruses with viral CD47 (vCD47).
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