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Mono- and tri-cationic porphyrin-monoclonal antibody conjugates: photodynamic activity and mechanism of action.

Smith K, Malatesti N, Cauchon N, Hunting D, Lecomte R, van Lier JE, Greenman J, Boyle RW - Immunology (2010)

Bottom Line: In vitro, all conjugates retained the phototoxicity of the porphyrin and the immunoreactivity of the antibody.Mechanistic studies showed that conjugates formed from the mono- and tri-cationic porphyrin and anti-CD104 antibody mediated apoptosis following irradiation with non-thermal red light of 630 ± 15 nm wavelength.This effect was not observed with Photofrin or with conjugates formed from the same photosensitizers conjugated to an irrelevant antibody.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Centre for Biomedical Research, University of Hull, Kingston-upon-Hull, UK.

ABSTRACT
Two cationic porphyrins bearing an isothiocyanate group for conjugation to monocolonal antibodies have been synthesized. The two porphyrins conjugated efficiently to three monoclonal antibodies (anti-CD104, anti-CD146 and anti-CD326), which recognize antigens commonly over-expressed on a range of tumour cells. In vitro, all conjugates retained the phototoxicity of the porphyrin and the immunoreactivity of the antibody. Mechanistic studies showed that conjugates formed from the mono- and tri-cationic porphyrin and anti-CD104 antibody mediated apoptosis following irradiation with non-thermal red light of 630 ± 15 nm wavelength. In vivo antibody conjugates caused suppression of human LoVo tumour growth in immunodeficient NIH III mice, similar to the commercial photodynamic therapy (PDT) agent Photofrin, but at administered photosensitizer doses that were more than two orders of magnitude lower. Positron emission tomography (PET) following PDT showed a large, early increase in uptake of (18) fluorodeoxyglucose (FDG) by tumours treated with the anti-CD104 conjugates. This effect was not observed with Photofrin or with conjugates formed from the same photosensitizers conjugated to an irrelevant antibody.

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Related in: MedlinePlus

Immunodeficient NIH III mice bearing two LoVo tumours (diameter 2–3 mm; one in each leg) were injected with Photofrin® (5 mg/kg) or conjugate (10 nmol/kg) 24 hr prior to irradiation: one tumour per mouse was irradiated while the second served as an unirradiated control. Tumour size was measured by calliper and growth was followed to 12 days post-irradiation. Tumour size for three mice per point was averaged and the standard error is shown.
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fig06: Immunodeficient NIH III mice bearing two LoVo tumours (diameter 2–3 mm; one in each leg) were injected with Photofrin® (5 mg/kg) or conjugate (10 nmol/kg) 24 hr prior to irradiation: one tumour per mouse was irradiated while the second served as an unirradiated control. Tumour size was measured by calliper and growth was followed to 12 days post-irradiation. Tumour size for three mice per point was averaged and the standard error is shown.

Mentions: Photodynamic treatment was conducted by intravenous injection of immunoconjugates, or Photofrin®, into mice bearing two tumours, one on each hind leg. One tumour was then irradiated, while the second was protected from light and acted as a control. Doses of immunoconjugates (10 nmol/kg) were based on injected photosensitizer concentrations, which were determined spectroscopically. Photofrin® was administered at a standard dose (5 mg/kg; equivalent to 8·3 μmol/kg) used for PDT treatment of tumour-bearing mice. Two relevant (anti-CD104-porphyrin 1 and anti-CD104-porphyrin-2) conjugates and two irrelevant (anti-CD146-porphyrin 1 and anti-CD146-porphyrin 2) conjugates (to act as controls) were investigated, and compared with Photofrin®. Figure 6 shows the growth of PDT-treated tumours for anti-CD104-porphyrin 1, anti-CD104-porphyrin 2, anti-CD146-porphyrin 1, anti-CD146-porphyrin 2, and Photofrin®, relative to non-irradiated control tumours on the same animal.


Mono- and tri-cationic porphyrin-monoclonal antibody conjugates: photodynamic activity and mechanism of action.

Smith K, Malatesti N, Cauchon N, Hunting D, Lecomte R, van Lier JE, Greenman J, Boyle RW - Immunology (2010)

Immunodeficient NIH III mice bearing two LoVo tumours (diameter 2–3 mm; one in each leg) were injected with Photofrin® (5 mg/kg) or conjugate (10 nmol/kg) 24 hr prior to irradiation: one tumour per mouse was irradiated while the second served as an unirradiated control. Tumour size was measured by calliper and growth was followed to 12 days post-irradiation. Tumour size for three mice per point was averaged and the standard error is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045661&req=5

fig06: Immunodeficient NIH III mice bearing two LoVo tumours (diameter 2–3 mm; one in each leg) were injected with Photofrin® (5 mg/kg) or conjugate (10 nmol/kg) 24 hr prior to irradiation: one tumour per mouse was irradiated while the second served as an unirradiated control. Tumour size was measured by calliper and growth was followed to 12 days post-irradiation. Tumour size for three mice per point was averaged and the standard error is shown.
Mentions: Photodynamic treatment was conducted by intravenous injection of immunoconjugates, or Photofrin®, into mice bearing two tumours, one on each hind leg. One tumour was then irradiated, while the second was protected from light and acted as a control. Doses of immunoconjugates (10 nmol/kg) were based on injected photosensitizer concentrations, which were determined spectroscopically. Photofrin® was administered at a standard dose (5 mg/kg; equivalent to 8·3 μmol/kg) used for PDT treatment of tumour-bearing mice. Two relevant (anti-CD104-porphyrin 1 and anti-CD104-porphyrin-2) conjugates and two irrelevant (anti-CD146-porphyrin 1 and anti-CD146-porphyrin 2) conjugates (to act as controls) were investigated, and compared with Photofrin®. Figure 6 shows the growth of PDT-treated tumours for anti-CD104-porphyrin 1, anti-CD104-porphyrin 2, anti-CD146-porphyrin 1, anti-CD146-porphyrin 2, and Photofrin®, relative to non-irradiated control tumours on the same animal.

Bottom Line: In vitro, all conjugates retained the phototoxicity of the porphyrin and the immunoreactivity of the antibody.Mechanistic studies showed that conjugates formed from the mono- and tri-cationic porphyrin and anti-CD104 antibody mediated apoptosis following irradiation with non-thermal red light of 630 ± 15 nm wavelength.This effect was not observed with Photofrin or with conjugates formed from the same photosensitizers conjugated to an irrelevant antibody.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Centre for Biomedical Research, University of Hull, Kingston-upon-Hull, UK.

ABSTRACT
Two cationic porphyrins bearing an isothiocyanate group for conjugation to monocolonal antibodies have been synthesized. The two porphyrins conjugated efficiently to three monoclonal antibodies (anti-CD104, anti-CD146 and anti-CD326), which recognize antigens commonly over-expressed on a range of tumour cells. In vitro, all conjugates retained the phototoxicity of the porphyrin and the immunoreactivity of the antibody. Mechanistic studies showed that conjugates formed from the mono- and tri-cationic porphyrin and anti-CD104 antibody mediated apoptosis following irradiation with non-thermal red light of 630 ± 15 nm wavelength. In vivo antibody conjugates caused suppression of human LoVo tumour growth in immunodeficient NIH III mice, similar to the commercial photodynamic therapy (PDT) agent Photofrin, but at administered photosensitizer doses that were more than two orders of magnitude lower. Positron emission tomography (PET) following PDT showed a large, early increase in uptake of (18) fluorodeoxyglucose (FDG) by tumours treated with the anti-CD104 conjugates. This effect was not observed with Photofrin or with conjugates formed from the same photosensitizers conjugated to an irrelevant antibody.

Show MeSH
Related in: MedlinePlus