Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy

Título traducido de la contribución: Análisis estructura-función y eficacia terapéutica de los anticuerpos contra la melanina fúngica para la radioinmunoterapia del melanoma

J. D. Nosanchuk, A. Jeyakumar, A. Ray, E. Revskaya, Z. Jiang, R. A. Bryan, K. J.H. Allen, R. Jiao, M. E. Malo, B. L. Gómez, A. Morgenstern, F. Bruchertseifer, D. Rickles, G. B. Thornton, A. Bowen, A. Casadevall, E. Dadachova

Resultado de la investigación: Contribución a RevistaArtículo

2 Citas (Scopus)

Resumen

El melanoma metastásico sigue siendo difícil de tratar a pesar de las recientes aprobaciones de varios medicamentos nuevos. Recientemente informamos resultados alentadores del ensayo clínico de fase I de radiomarcados con 188Re murine monoclonal IgM 6D2 a la melanina en pacientes con melanoma en estadio III/IV. Posteriormente generamos una nueva IgG murina 8C3 a melanina. Los IgG son más susceptibles a la humanización y a las cGMP (buenas prácticas de fabricación actuales) que los IgM, por lo que realizamos un análisis estructural comparativo de las IgM 6D2 e IgG 8C3 fijadoras de melanina. La eficacia terapéutica de la 8C3 reetiquetada con 213Bi y 188R y su comparación con la inmunoterapia antiCTLA4 se realizó en el modelo de melanoma murino B16-F10. Las estructuras primarias de estos anticuerpos revelaron una homología significativa, con los CDRs conteniendo un alto porcentaje de aminoácidos cargados positivamente. El modelo 8C3 tiene una superficie de unión cargada negativamente y un número significativo de residuos aromáticos en su dominio H3, lo que sugiere que las interacciones hidrofóbicas contribuyen a la interacción anticuerpo-melanina. La IgG 8C3 radiomarcada mostró una eficacia terapéutica significativa en el melanoma murino, seguridad para los tejidos sanos que contienen melanina y una comparación favorable con el anticuerpo antiCTLA4. Hemos demostrado que la unión de anticuerpos a la melanina depende tanto de las interacciones de carga como de las hidrofóbicas, mientras que los datos in vivo apoyan el desarrollo adicional de la IgG 8C3 como reactivo de radioinmunoterapia para el melanoma metastásico.
Idioma originalEnglish (US)
Número de artículo5466
PublicaciónScientific Reports
Volumen8
N.º1
DOI
EstadoPublished - abr 3 2018

All Science Journal Classification (ASJC) codes

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Nosanchuk, J. D., Jeyakumar, A., Ray, A., Revskaya, E., Jiang, Z., Bryan, R. A., ... Dadachova, E. (2018). Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy. Scientific Reports, 8(1), [5466]. https://doi.org/10.1038/s41598-018-23889-z
Nosanchuk, J. D. ; Jeyakumar, A. ; Ray, A. ; Revskaya, E. ; Jiang, Z. ; Bryan, R. A. ; Allen, K. J.H. ; Jiao, R. ; Malo, M. E. ; Gómez, B. L. ; Morgenstern, A. ; Bruchertseifer, F. ; Rickles, D. ; Thornton, G. B. ; Bowen, A. ; Casadevall, A. ; Dadachova, E. / Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy. En: Scientific Reports. 2018 ; Vol. 8, N.º 1.
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title = "Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy",
abstract = "Metastatic melanoma remains difficult to treat despite recent approvals of several new drugs. Recently we reported encouraging results of Phase I clinical trial of radiolabeled with 188Re murine monoclonal IgM 6D2 to melanin in patients with Stage III/IV melanoma. Subsequently we generated a novel murine IgG 8C3 to melanin. IgGs are more amenable to humanization and cGMP (current Good Manufacturing Practice) manufacturing than IgMs. We performed comparative structural analysis of melanin-binding IgM 6D2 and IgG 8C3. The therapeutic efficacy of 213Bi- And 188Re-labeled 8C3 and its comparison with anti-CTLA4 immunotherapy was performed in B16-F10 murine melanoma model. The primary structures of these antibodies revealed significant homology, with the CDRs containing a high percentage of positively charged amino acids. The 8C3 model has a negatively charged binding surface and significant number of aromatic residues in its H3 domain, suggesting that hydrophobic interactions contribute to the antibody-melanin interaction. Radiolabeled IgG 8C3 showed significant therapeutic efficacy in murine melanoma, safety towards healthy melanin-containing tissues and favorable comparison with the anti-CTLA4 antibody. We have demonstrated that antibody binding to melanin relies on both charge and hydrophobic interactions while the in vivo data supports further development of 8C3 IgG as radioimmunotherapy reagent for metastatic melanoma.",
author = "Nosanchuk, {J. D.} and A. Jeyakumar and A. Ray and E. Revskaya and Z. Jiang and Bryan, {R. A.} and Allen, {K. J.H.} and R. Jiao and Malo, {M. E.} and G{\'o}mez, {B. L.} and A. Morgenstern and F. Bruchertseifer and D. Rickles and Thornton, {G. B.} and A. Bowen and A. Casadevall and E. Dadachova",
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Nosanchuk, JD, Jeyakumar, A, Ray, A, Revskaya, E, Jiang, Z, Bryan, RA, Allen, KJH, Jiao, R, Malo, ME, Gómez, BL, Morgenstern, A, Bruchertseifer, F, Rickles, D, Thornton, GB, Bowen, A, Casadevall, A & Dadachova, E 2018, 'Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy', Scientific Reports, vol. 8, n.º 1, 5466. https://doi.org/10.1038/s41598-018-23889-z

Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy. / Nosanchuk, J. D.; Jeyakumar, A.; Ray, A.; Revskaya, E.; Jiang, Z.; Bryan, R. A.; Allen, K. J.H.; Jiao, R.; Malo, M. E.; Gómez, B. L.; Morgenstern, A.; Bruchertseifer, F.; Rickles, D.; Thornton, G. B.; Bowen, A.; Casadevall, A.; Dadachova, E.

En: Scientific Reports, Vol. 8, N.º 1, 5466, 03.04.2018.

Resultado de la investigación: Contribución a RevistaArtículo

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T1 - Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy

AU - Nosanchuk, J. D.

AU - Jeyakumar, A.

AU - Ray, A.

AU - Revskaya, E.

AU - Jiang, Z.

AU - Bryan, R. A.

AU - Allen, K. J.H.

AU - Jiao, R.

AU - Malo, M. E.

AU - Gómez, B. L.

AU - Morgenstern, A.

AU - Bruchertseifer, F.

AU - Rickles, D.

AU - Thornton, G. B.

AU - Bowen, A.

AU - Casadevall, A.

AU - Dadachova, E.

PY - 2018/4/3

Y1 - 2018/4/3

N2 - Metastatic melanoma remains difficult to treat despite recent approvals of several new drugs. Recently we reported encouraging results of Phase I clinical trial of radiolabeled with 188Re murine monoclonal IgM 6D2 to melanin in patients with Stage III/IV melanoma. Subsequently we generated a novel murine IgG 8C3 to melanin. IgGs are more amenable to humanization and cGMP (current Good Manufacturing Practice) manufacturing than IgMs. We performed comparative structural analysis of melanin-binding IgM 6D2 and IgG 8C3. The therapeutic efficacy of 213Bi- And 188Re-labeled 8C3 and its comparison with anti-CTLA4 immunotherapy was performed in B16-F10 murine melanoma model. The primary structures of these antibodies revealed significant homology, with the CDRs containing a high percentage of positively charged amino acids. The 8C3 model has a negatively charged binding surface and significant number of aromatic residues in its H3 domain, suggesting that hydrophobic interactions contribute to the antibody-melanin interaction. Radiolabeled IgG 8C3 showed significant therapeutic efficacy in murine melanoma, safety towards healthy melanin-containing tissues and favorable comparison with the anti-CTLA4 antibody. We have demonstrated that antibody binding to melanin relies on both charge and hydrophobic interactions while the in vivo data supports further development of 8C3 IgG as radioimmunotherapy reagent for metastatic melanoma.

AB - Metastatic melanoma remains difficult to treat despite recent approvals of several new drugs. Recently we reported encouraging results of Phase I clinical trial of radiolabeled with 188Re murine monoclonal IgM 6D2 to melanin in patients with Stage III/IV melanoma. Subsequently we generated a novel murine IgG 8C3 to melanin. IgGs are more amenable to humanization and cGMP (current Good Manufacturing Practice) manufacturing than IgMs. We performed comparative structural analysis of melanin-binding IgM 6D2 and IgG 8C3. The therapeutic efficacy of 213Bi- And 188Re-labeled 8C3 and its comparison with anti-CTLA4 immunotherapy was performed in B16-F10 murine melanoma model. The primary structures of these antibodies revealed significant homology, with the CDRs containing a high percentage of positively charged amino acids. The 8C3 model has a negatively charged binding surface and significant number of aromatic residues in its H3 domain, suggesting that hydrophobic interactions contribute to the antibody-melanin interaction. Radiolabeled IgG 8C3 showed significant therapeutic efficacy in murine melanoma, safety towards healthy melanin-containing tissues and favorable comparison with the anti-CTLA4 antibody. We have demonstrated that antibody binding to melanin relies on both charge and hydrophobic interactions while the in vivo data supports further development of 8C3 IgG as radioimmunotherapy reagent for metastatic melanoma.

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