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Tumor treatment by pHLIP-targeted antigen delivery

Targeted antigen delivery allows activation of the immune system to kill cancer cells. Here we report the targeted delivery of various epitopes, including a peptide, a small molecule, and a sugar, to tumors by pH Low Insertion Peptides (pHLIPs), which respond to surface acidity and insert to span th...

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Autores principales: DuPont, Michael, Visca, Hannah, Moshnikova, Anna, Engelman, Donald M., Reshetnyak, Yana K., Andreev, Oleg A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9853002/
https://www.ncbi.nlm.nih.gov/pubmed/36686229
http://dx.doi.org/10.3389/fbioe.2022.1082290
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author DuPont, Michael
Visca, Hannah
Moshnikova, Anna
Engelman, Donald M.
Reshetnyak, Yana K.
Andreev, Oleg A.
author_facet DuPont, Michael
Visca, Hannah
Moshnikova, Anna
Engelman, Donald M.
Reshetnyak, Yana K.
Andreev, Oleg A.
author_sort DuPont, Michael
collection PubMed
description Targeted antigen delivery allows activation of the immune system to kill cancer cells. Here we report the targeted delivery of various epitopes, including a peptide, a small molecule, and a sugar, to tumors by pH Low Insertion Peptides (pHLIPs), which respond to surface acidity and insert to span the membranes of metabolically activated cancer and immune cells within tumors. Epitopes linked to the extracellular ends of pH Low Insertion Peptide peptides were positioned at the surfaces of tumor cells and were recognized by corresponding anti-epitope antibodies. Special attention was devoted to the targeted delivery of the nine residue HA peptide epitope from the Flu virus hemagglutinin. The HA sequence is not present in the human genome, and immunity is readily developed during viral infection or immunization with KLH-HA supplemented with adjuvants. We tested and refined a series of double-headed HA-pHLIP agents, where two HA epitopes were linked to a single pH Low Insertion Peptide peptide via two Peg12 or Peg24 polymers, which enable HA epitopes to engage both antibody binding sites. HA-epitopes positioned at the surfaces of tumor cells remain exposed to the extracellular space for 24–48 h and are then internalized. Different vaccination schemes and various adjuvants, including analogs of FDA approved adjuvants, were tested in mice and resulted in a high titer of anti-HA antibodies. Anti-HA antibody binds HA-pHLIP in blood and travels as a complex leading to significant tumor targeting with no accumulation in organs and to hepatic clearance. HA-pHLIP agents induced regression of 4T1 triple negative breast tumor and B16F10 MHC-I negative melanoma tumors in immunized mice. The therapeutic efficacy potentially is limited by the drop of the level of anti-HA antibodies in the blood to background level after three injections of HA-pHLIP. We hypothesize that additional boosts would be required to keep a high titer of anti-HA antibodies to enhance efficacy. pH Low Insertion Peptide-targeted antigen therapy may provide an opportunity to treat tumors unresponsive to T cell based therapies, having a small number of neo-antigens, or deficient in MHC-I presentation at the surfaces of cancer cells either alone or in combination with other approaches.
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spelling pubmed-98530022023-01-21 Tumor treatment by pHLIP-targeted antigen delivery DuPont, Michael Visca, Hannah Moshnikova, Anna Engelman, Donald M. Reshetnyak, Yana K. Andreev, Oleg A. Front Bioeng Biotechnol Bioengineering and Biotechnology Targeted antigen delivery allows activation of the immune system to kill cancer cells. Here we report the targeted delivery of various epitopes, including a peptide, a small molecule, and a sugar, to tumors by pH Low Insertion Peptides (pHLIPs), which respond to surface acidity and insert to span the membranes of metabolically activated cancer and immune cells within tumors. Epitopes linked to the extracellular ends of pH Low Insertion Peptide peptides were positioned at the surfaces of tumor cells and were recognized by corresponding anti-epitope antibodies. Special attention was devoted to the targeted delivery of the nine residue HA peptide epitope from the Flu virus hemagglutinin. The HA sequence is not present in the human genome, and immunity is readily developed during viral infection or immunization with KLH-HA supplemented with adjuvants. We tested and refined a series of double-headed HA-pHLIP agents, where two HA epitopes were linked to a single pH Low Insertion Peptide peptide via two Peg12 or Peg24 polymers, which enable HA epitopes to engage both antibody binding sites. HA-epitopes positioned at the surfaces of tumor cells remain exposed to the extracellular space for 24–48 h and are then internalized. Different vaccination schemes and various adjuvants, including analogs of FDA approved adjuvants, were tested in mice and resulted in a high titer of anti-HA antibodies. Anti-HA antibody binds HA-pHLIP in blood and travels as a complex leading to significant tumor targeting with no accumulation in organs and to hepatic clearance. HA-pHLIP agents induced regression of 4T1 triple negative breast tumor and B16F10 MHC-I negative melanoma tumors in immunized mice. The therapeutic efficacy potentially is limited by the drop of the level of anti-HA antibodies in the blood to background level after three injections of HA-pHLIP. We hypothesize that additional boosts would be required to keep a high titer of anti-HA antibodies to enhance efficacy. pH Low Insertion Peptide-targeted antigen therapy may provide an opportunity to treat tumors unresponsive to T cell based therapies, having a small number of neo-antigens, or deficient in MHC-I presentation at the surfaces of cancer cells either alone or in combination with other approaches. Frontiers Media S.A. 2023-01-06 /pmc/articles/PMC9853002/ /pubmed/36686229 http://dx.doi.org/10.3389/fbioe.2022.1082290 Text en Copyright © 2023 DuPont, Visca, Moshnikova, Engelman, Reshetnyak and Andreev. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Bioengineering and Biotechnology
DuPont, Michael
Visca, Hannah
Moshnikova, Anna
Engelman, Donald M.
Reshetnyak, Yana K.
Andreev, Oleg A.
Tumor treatment by pHLIP-targeted antigen delivery
title Tumor treatment by pHLIP-targeted antigen delivery
title_full Tumor treatment by pHLIP-targeted antigen delivery
title_fullStr Tumor treatment by pHLIP-targeted antigen delivery
title_full_unstemmed Tumor treatment by pHLIP-targeted antigen delivery
title_short Tumor treatment by pHLIP-targeted antigen delivery
title_sort tumor treatment by phlip-targeted antigen delivery
topic Bioengineering and Biotechnology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9853002/
https://www.ncbi.nlm.nih.gov/pubmed/36686229
http://dx.doi.org/10.3389/fbioe.2022.1082290
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