Evaluation of biodistribution and efficacy for targeting radiolabeled compounds
I. The purpose of the experiment/project:
The aim of this study is to evaluate the pharmacokinetic profile, biodistributuion and efficacy of novel targeting antibody-chelator conjugates. A new target with big potential benefit from for radioimmunotherapy has been identified. Several antibody-chelator conjugated has been produced and screened in vitro. In this study we aim to select one of these candidates for further development activities.
II. The expected adverse effects on the animals:
Three main adverse effects for the mice in this experiment are ulcerations of the tumors and weight reduction and reduction in white blood cell count due to toxicity. To eliminate the adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of ulcer, distress or 15% weight reduction. All doses used in this study are below the doses causing dose-limiting toxicity.
III. The expected scientific benefits or benefits for society:
A new targeting radiolabelled antibody-chelator conjugate for treatment of cancer expressing a target with high potential for radioimmutherapy. Currently, these patients are limited in terms of treatment option and there is a significant unmet medical need for treatment options for these patients.
IV. The number of animals and species:
In this study we aim to utilize a three different cancer models inoculated subcutaneously in Rj:NMRI-Foxn1nu/nu mice with different properties with regards to target expression, tumor physiology and growth rate. Both the PK/biodistribution and efficacy studies of will be performed. For PK/biodistribution we will perform 4 studies with 90, 60, 45 and 30 animals, respectively. The purpose of the studies is selection of the chelator, selection of the mAb clone and validation of the development candidate. In total for PK/biodistribution part we need 225 animals. For efficacy study we will utilize 50 animals per model, comparing tumor growth inhibition properties for radiolabelled antibody-chelator conjugate at 3 dose levels with vehicle and radiolabelled isotype control conjugate. In total for efficacy part we need 150 mice. For both parts of the study we need 375 tumor-bearing animals. Given the average take rate for the xenograft models we apply for 535 animals in this study
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies will be conducted to prove the efficacy, characterization and specific killing for all 3 cell lines before the conduction of the in vivo experiments. We have already established all 3 models in vivo, and have good knowledge of this models about group size, timing of treatment initiation etc. The number of mice in both efficacy and biodistribution parts of the study are reduced to minimum. The technicians conducting the study have long experience with similar studies using well-refined techniques.
The aim of this study is to evaluate the pharmacokinetic profile, biodistributuion and efficacy of novel targeting antibody-chelator conjugates. A new target with big potential benefit from for radioimmunotherapy has been identified. Several antibody-chelator conjugated has been produced and screened in vitro. In this study we aim to select one of these candidates for further development activities.
II. The expected adverse effects on the animals:
Three main adverse effects for the mice in this experiment are ulcerations of the tumors and weight reduction and reduction in white blood cell count due to toxicity. To eliminate the adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of ulcer, distress or 15% weight reduction. All doses used in this study are below the doses causing dose-limiting toxicity.
III. The expected scientific benefits or benefits for society:
A new targeting radiolabelled antibody-chelator conjugate for treatment of cancer expressing a target with high potential for radioimmutherapy. Currently, these patients are limited in terms of treatment option and there is a significant unmet medical need for treatment options for these patients.
IV. The number of animals and species:
In this study we aim to utilize a three different cancer models inoculated subcutaneously in Rj:NMRI-Foxn1nu/nu mice with different properties with regards to target expression, tumor physiology and growth rate. Both the PK/biodistribution and efficacy studies of will be performed. For PK/biodistribution we will perform 4 studies with 90, 60, 45 and 30 animals, respectively. The purpose of the studies is selection of the chelator, selection of the mAb clone and validation of the development candidate. In total for PK/biodistribution part we need 225 animals. For efficacy study we will utilize 50 animals per model, comparing tumor growth inhibition properties for radiolabelled antibody-chelator conjugate at 3 dose levels with vehicle and radiolabelled isotype control conjugate. In total for efficacy part we need 150 mice. For both parts of the study we need 375 tumor-bearing animals. Given the average take rate for the xenograft models we apply for 535 animals in this study
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies will be conducted to prove the efficacy, characterization and specific killing for all 3 cell lines before the conduction of the in vivo experiments. We have already established all 3 models in vivo, and have good knowledge of this models about group size, timing of treatment initiation etc. The number of mice in both efficacy and biodistribution parts of the study are reduced to minimum. The technicians conducting the study have long experience with similar studies using well-refined techniques.