Compositions and methods for treatment of pain
AssigneesPresident and Fellows of Harvard College, Massachusetts Institute of Technology
InventorsR. John Collier, Isaac Chiu, Bradley L. Pentelute
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Abstract
Embodied herein are engineered fusion proteins that bind and target nociceptor neurons, compositions comprising these engineered fusion proteins, and methods for treatment of pain using these engineered fusion proteins or compositions containing the engineered fusion proteins. The engineered fusion proteins contain domains derived from protein toxins such as the anthrax toxin, clostridial botulinum family of toxins, disulphide-containing toxins, and AB component type toxins.
Claims88
A fusion protein comprising:
- a) a botulinum neurotoxin (BTx) or a tetanus neurotoxin (TTx), and
- b) an anthrax toxin protective antigen (PA), or a C-terminal receptor-binding domain of PA,
- wherein part (a) and (b) are linked or fused together.
A fusion protein comprising:
- a) a non-cytotoxic protease, which protease is capable of cleaving a SNARE protein in a nociceptor neuron;
- and
- b) a protein capable of binding to an anthrax toxin protective antigen (PA) or a fragment thereof,
- wherein the PA or fragment binds a receptor expressed on the nociceptor neuron.
A fusion protein comprising:
- a) a disulfide-containing peptide toxin (these include the channel blocking toxins having a cysteine-knot motif), which is capable of blocking ion channels in a nociceptor neuron;
- and
- b) a targeting moiety (TM) that is capable of binding to a binding site on the nociceptor neuron, wherein the nociceptor neuron expresses said ion channels therein (e.g., sodium or calcium or both sodium and calcium);
26-29. (canceled)
A fusion protein comprising:
- a) a disulfide-containing peptide toxin (this are channel blocking toxin having a cysteine-knot motif), which is capable of blocking sodium or calcium or both sodium and calcium channels in a nociceptor neuron;
- and
- b) a protein capable of binding to an anthrax toxin protective antigen (PA) or a fragment thereof,
- wherein the fragment binds a receptor expressed on the nociceptor neuron.
34-37. (canceled)
A fusion protein comprising:
- a) an AB toxin;
- b) an anthrax toxin protective antigen (PA) or a fragment thereof, wherein the PA or fragment binds a receptor expressed on the nociceptor neuron;
- and
- c) a Translocation domain (TL) that is capable of translocating the protease from within an endosome, across the endosomal membrane and into the cytosol of the nociceptor neuron.
(canceled)
43-49. (canceled)
A method of treating pain comprising administering to a subject in need thereof, native mature anthrax toxin protective antigen (PA) and anthrax toxin edema factor (EF), anthrax toxin lethal factor (LF) or any combination thereof.
52-69. (canceled)
A fusion protein comprising:
- a) a botulinum neurotoxin N-terminal enzymatic domain of a botulinum neurotoxin (BTx) moiety (L chain of BTx), and
- b) a N-terminal domain (LFn) of anthrax toxin lethal factor, which domain binds to oligomeric forms of PA63, the proteolytically activated form of anthrax PA;
- or the N-terminal domain (EFn) of anthrax toxin edema factor, which domain binds to oligomeric forms of PA63, the proteolytically activated form of anthrax PAthe enzymatic domain,
- wherein part (a) is linked N-terminally or C-terminally or both N-terminally and C-terminally to part (b).
76-79. (canceled)
(canceled)
83-85. (canceled)
A fusion protein comprising:
- a) anthrax toxin protective antigen (PA);
- an anthrax toxin protective antigen C-terminal receptor binding domain (PAd4);
- or a nociceptor neuron-binding protein linked to,
- b) a disulfide-containing peptide toxin.
(canceled)
90-104. (canceled)
A fusion protein comprising a disulfide-containing peptide toxin operably linked N-terminally or C-terminally or both N-terminally and C-terminally, or chemically crosslinked at one or more sites to the N-terminal domain (LFn) of anthrax toxin lethal factor, which domain binds to oligomeric forms of PA63, the proteolytically activated form of anthrax PA;
- or the N-terminal domain (EFn) of anthrax toxin edema factor, which domain binds to oligomeric forms of PA63, the proteolytically activated form of anthrax PA.
107-115. (canceled)
A fusion protein comprising an AB toxin fused to a linker peptide operably linked to a C-terminal receptor-binding domain of anthrax toxin protective antigen (PAd4 domain), wherein the fusion protein further comprises a translocation domain, a holotoxin or a mutant form of the holotoxin that has the toxin receptor-binding function of the AB toxin negated.
117-121. (canceled)
123-131. (canceled)
A fusion protein comprising an N-terminal enzymatic domain (Chain A) together with the translocation/pore-forming domain from a tetanus neurotoxin (TTx) operably linked to a C-terminal receptor-binding domain of anthrax toxin protective antigen (PAd4 domain).
134-138. (canceled)
140-148. (canceled)
156-164. (canceled)
(canceled)
A fusion protein comprising:
- a. a botulinum neurotoxin (BTx) moiety, wherein the BTx moiety comprises an enzymatic moiety and a translocation domain and
- b. a targeting moiety comprising a C-terminal receptor-binding domain of an anthrax toxin protective antigen (PA), wherein the C-terminal receptor-binding domain of PA comprises a PAd4 domain, wherein part (a) and (b) are linked or fused together.
A nucleic acid encoding a fusion protein comprising:
- a. a botulinum neurotoxin (BTx) moiety that comprises an enzymatic moiety and a translocation domain;
- and
- b. a targeting moiety comprising a C-terminal receptor-binding domain of anthrax toxin protective antigen (PA), wherein the C-terminal receptor-binding domain of PA comprises a PAd4 domain,
- wherein part (a) and (b) are linked or fused together.
Dependencies are inferred from the claim text.