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 conjugate. We have identified a novel combination of a targeting monoclonal antibody and a radioisotope that together have a great potential to benefit cancer patients with currently unmet medical need. Several antibody-chelator conjugates has been produced, radiolabelled and screened in vitro. In this study we aim evaluate properties of these radiolabelled conjugates and select one development candidate for further development activities.
II. The expected adverse effects on the animals:
The main adverse effects for the mice in this experiment are weight reduction, reduction in white blood cell count and effects of supplemental hormonal treatment. To eliminate these adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of discomfort, separate or sacrifice animals in case of morbid behavioral changes or sacrifice the animals in case of body weight reduction of more than 15%. All doses of radiolabelled conjugates used in this study are below the doses causing radioactivity-associated toxicity for the selected radionuclide.
III. The expected scientific benefits or benefits for society:
As a result of this study we will select one novel targeting radiolabelled antibody-chelator conjugate for treatment of cancer expressing a target with high potential for radioimmunotherapy. Currently, these patients are limited in terms of treatment option for the late lines of therapy 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 two different cancer models with different properties with regards to target expression, tumor physiology and growth rate. Both the PK/biodistribution and efficacy studies will be performed. In PK/biodistribution part we will perform 2 studies with 90 and 30 animals. The purpose of the studies is to select a mAb-chelator combination and to validate the selected development candidate. In total for PK/biodistribution part we need 90+30=120 animals. In efficacy part we will perform evaluation of the anti-tumor efficacy with single dose (50 mice) and multiple doses (60 mice) treatment regimes. We will need 50+60=110 animals per model, in total 220 mice for 2 models. For both parts of the study we need 120+220=340 tumor-bearing animals. Given the average take rate for the selected xenograft models around 85% we apply for 340/0.85=400 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 characterize the conjugates and demonstrate specific killing in both cell lines before conducting the in vivo experiments. We have previously established both models in vivo and have good knowledge of these models in terms of group size, timing to treatment start and other factors helping to reduce variability. 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 conjugate. We have identified a novel combination of a targeting monoclonal antibody and a radioisotope that together have a great potential to benefit cancer patients with currently unmet medical need. Several antibody-chelator conjugates has been produced, radiolabelled and screened in vitro. In this study we aim evaluate properties of these radiolabelled conjugates and select one development candidate for further development activities.
II. The expected adverse effects on the animals:
The main adverse effects for the mice in this experiment are weight reduction, reduction in white blood cell count and effects of supplemental hormonal treatment. To eliminate these adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of discomfort, separate or sacrifice animals in case of morbid behavioral changes or sacrifice the animals in case of body weight reduction of more than 15%. All doses of radiolabelled conjugates used in this study are below the doses causing radioactivity-associated toxicity for the selected radionuclide.
III. The expected scientific benefits or benefits for society:
As a result of this study we will select one novel targeting radiolabelled antibody-chelator conjugate for treatment of cancer expressing a target with high potential for radioimmunotherapy. Currently, these patients are limited in terms of treatment option for the late lines of therapy 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 two different cancer models with different properties with regards to target expression, tumor physiology and growth rate. Both the PK/biodistribution and efficacy studies will be performed. In PK/biodistribution part we will perform 2 studies with 90 and 30 animals. The purpose of the studies is to select a mAb-chelator combination and to validate the selected development candidate. In total for PK/biodistribution part we need 90+30=120 animals. In efficacy part we will perform evaluation of the anti-tumor efficacy with single dose (50 mice) and multiple doses (60 mice) treatment regimes. We will need 50+60=110 animals per model, in total 220 mice for 2 models. For both parts of the study we need 120+220=340 tumor-bearing animals. Given the average take rate for the selected xenograft models around 85% we apply for 340/0.85=400 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 characterize the conjugates and demonstrate specific killing in both cell lines before conducting the in vivo experiments. We have previously established both models in vivo and have good knowledge of these models in terms of group size, timing to treatment start and other factors helping to reduce variability. 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.