Biodistribution of a Radiolabeled Antibody in Mice as an Approach to Evaluating Antibody Pharmacokinetics

Allen, Kevin; Jiao, Rubin; Malo, Mackenzie E.; Frank, Connor; Dadachova, Ekaterina

doi:10.3390/pharmaceutics10040262

Cited by 22 publications

(23 citation statements)

References 20 publications

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“…Conjugation of BCA CHXA" to h8C3 antibody and radiolabeling with 213 Bi. The conjugation of CHXA" to h8C3 was performed as in [23] with a minor alteration. A 10-fold molar excess of CHXA" was used in place of a 5-fold excess.…”

Section: Methodsmentioning

confidence: 99%

Evaluating the Combination of Radioimmunotherapy and Immunotherapy in a Melanoma Mouse Model

Jiao

Allen

Malo

et al. 2020

IJMS

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Immunotherapy has changed the oncology landscape during the last decade and become standard of care for several cancers. The combinations of immunotherapy with other treatment modalities are also being investigated. One of the challenges to investigate such combinations is to identify suitable mouse models for the pre-clinical experiments. In the past, we and other researchers showed that murine B16-F10 melanoma in C57Bl6 mice is refractory to treatment with immune checkpoint inhibitors. In this work we studied the suitability of an alternative syngeneic model, Cloudman S91 murine melanoma in DBA/2 mouse (DBA/2NCrl), to study the combination of immunotherapy targeting PD-1 and radioimmunotherapy targeting melanin. DBA/2 male and female mice were injected subcutaneously with 3–6 million Cloudman S91 cells. When the tumors reached ~150 mm3 volume, the animals were treated intraperitoneally with PBS (sham), h8C3 unlabeled (cold) antibody to melanin, immunotherapy with anti-PD-1 antibody, radioimmunotherapy with 213Bismuth (213Bi)-labeled h8C3 antibody, or several combinations of immunotherapy and radioimmunotherapy. Treatments with immunotherapy alone produced very modest effect on the tumor size, while combination therapy resulted in significant slowing down of the tumor growth, increased animal survival, and no decrease in animal body weight. We conclude that Cloudman S91 murine melanoma in DBA/2 mouse is a suitable model to evaluate combination of immunotherapy of melanoma with tangentially targeted treatments.

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Section: Methodsmentioning

confidence: 99%

Evaluating the Combination of Radioimmunotherapy and Immunotherapy in a Melanoma Mouse Model

Jiao

Allen

Malo

et al. 2020

IJMS

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“…400-2, 2G8 and MOPC21 antibodies were first conjugated to a chelating agent C-functionalized trans-cyclohexyldiethylenetriamine pentaacetic acid derivative (CHXA ) (Macrocyclics, San Antonio, TX, United States) with a 10 molar excess to enable its subsequent radiolabeling with 111 In, 177 Lu or 213 Bi. Conjugation and labeling was carried out according to a previously published method (Allen et al, 2018. In short, the conjugation reaction was carried out for 1.5 h at 37 • C in sodium carbonate buffer at pH 8.5.…”

Section: Radionuclides and Radiolabeling Of Antibodiesmentioning

confidence: 99%

“…Lungs were then isolated. Radioactivity was then measured for each lung tissue using PerkinElmer© Gamma Counter in reference to the radiolabeled antibody standard as described (Allen et al, 2018). Radioactivity was then determined per unit weight of each isolated lung.…”

Section: Determination Of the Binding Ability Of Radiolabeled Antibodmentioning

confidence: 99%

Radioimmunotherapy of Blastomycosis in a Mouse Model With a (1→3)-β-Glucans Targeting Antibody

et al. 2020

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Invasive fungal infections (IFI) cause devastating morbidity and mortality, with the number of IFIs more than tripling since 1979. Our laboratories were the first to demonstrate that radiolabeled microorganism-specific monoclonal antibodies are highly effective for treatment of experimental fungal, bacterial and viral infections. Later we proposed to utilize surface expressed pan-antigens shared by major IFI-causing pathogens such as beta-glucans as RIT targets. Here we evaluated in vivo RIT targeting beta-glucan in Blastomyces dermatitidis which causes serious infections in immunocompromised and immunocompetent individuals and in companion dogs. B. dermatitidis cells were treated with the 400-2 antibody to (1→3)-β-glucans radiolabeled with the beta-emitter 177Lutetium ( 177 Lu) and alpha-emitter 213Bismuth ( 213 Bi) and the efficacy of cell kill was determined by colony forming units (CFUs). To determine the antigen-specific localization of the 400-2 antibody in vivo, C57BL6 mice were infected intratracheally with 2 × 10 5 B. dermatitidis cells and given 111 In-400-2 antibody 24 h later. To evaluate the killing of B. dermatitidis cells with RIT, intratracheally infected mice were treated with 150 µCi 213 Bi-400-2 and their lungs analyzed for CFUs 96 h post-infection. 213 Bi-400-2 proved to be more effective in killing B. dermatitidis cells in vitro than 177 Lu-400-2. Three times more 111 In-400-2 accumulated in the lungs of infected mice, than in the non-infected ones. 213 Bi-400-2 lowered the fungal burden in the lungs of infected mice more than 2 logs in comparison with non-treated infected controls. In conclusion, our results demonstrate the ability of an anti-(1-3)-beta-D-glucan antibody armed with an alpha-emitter 213 Bi to selectively kill B. dermatitidis cells in vitro and in vivo. These first in vivo results of the effectiveness of RIT targeting pan-antigens on fungal pathogens warrant further investigation.

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“…Unlabeled 4497 and Palivizumab mAbs were also used as controls. MAbs 4497 and Palivizumab were conjugated to bifunctional chelating agents CHXA" or DOTA (Macrocyclics, USA) using a 10-or 20-fold molar excess over mAb as described earlier [11]. Conjugated antibody was radiolabeled with three different radioisotopes, 213 Bismuth, 177 Lutetium and 225 Actinium.…”

Section: Antibodies and Radiolabelingmentioning

confidence: 99%

Radioimmunotherapy of methicillin-resistant Staphylococcus aureus in planktonic state and biofilms

et al. 2020

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Background Implant associated infections such as periprosthetic joint infections are difficult to treat as the bacteria form a biofilm on the prosthetic material. This biofilm complicates surgical and antibiotic treatment. With rising antibiotic resistance, alternative treatment options are needed to treat these infections in the future. The aim of this article is to provide proof-ofprinciple data required for further development of radioimmunotherapy for non-invasive treatment of implant associated infections. Methods Planktonic cells and biofilms of Methicillin-resistant staphylococcus aureus are grown and treated with radioimmunotherapy. The monoclonal antibodies used, target wall teichoic acids that are cell and biofilm specific. Three different radionuclides in different doses were used. Viability and metabolic activity of the bacterial cells and biofilms were measured by CFU dilution and XTT reduction. Results Alpha-RIT with Bismuth-213 showed significant and dose dependent killing in both planktonic MRSA and biofilm. When planktonic bacteria were treated with 370 kBq of 213 Bi-RIT 99% of the bacteria were killed. Complete killing of the bacteria in the biofilm was seen at 185 kBq. Beta-RIT with Lutetium-177 and Actinium-225 showed little to no significant killing. Conclusion Our results demonstrate the ability of specific antibodies loaded with an alpha-emitter Bismuth-213 to selectively kill staphylococcus aureus cells in vitro in both planktonic and biofilm

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Biodistribution of a Radiolabeled Antibody in Mice as an Approach to Evaluating Antibody Pharmacokinetics

Cited by 22 publications

References 20 publications

Evaluating the Combination of Radioimmunotherapy and Immunotherapy in a Melanoma Mouse Model

Evaluating the Combination of Radioimmunotherapy and Immunotherapy in a Melanoma Mouse Model

Radioimmunotherapy of Blastomycosis in a Mouse Model With a (1→3)-β-Glucans Targeting Antibody

Radioimmunotherapy of methicillin-resistant Staphylococcus aureus in planktonic state and biofilms

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