Forsøksdyr: Selection of antibody lead candidate for a stromal target and evaluation of efficacy in xenograft model


Godkjenningsdato 05.06.2018

. The purpose of the experiment/project:
The purpose of this experiment is to select an antibody clone for TTC lead candidate for further development and evaluate it's pharmacokinetic properties and efficacy in xenograft cancer model.

II. The expected adverse effects on the animals:
Three main adverse effects for the mice in this experiment are ulcerations of the tumors, weight reduction and reduction in white blood cell count. To eliminate the adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of ulcer or 15% weight reduction. White blood cell count didn't lead to any noticeable change in animal well-being. Else, animals will be immediately sacrificed with first signs of distress.

III. The expected scientific benefits or benefits for society:
The target is selectively expressed in stromal tissue of epithelial cancers. Targeting it allows delivery of Th227, an alpha emitting isotope. This allows killing of resistant cancer cells, especially in triple negative breast cancer where choices of targets are limited.

IV. The number of animals and species:
In this study we aim to evaluate up to 5 different clones: 5 clones are currently in in vitro evaluation and available from April 2018. In total this evaluation will require 162 mice. After a lead candidate will be selected, an in vivo efficacy in xenograft cancer model will be performed requiring 50 mice. If successful, 3 additional models will be evaluated, requiring 70 mice each. In total, an efficacy part of the study, if fully completed, will require 260 mice. Accounting for take rate around 80% for both part of the study we would need 470 mice.

V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies were conducted to prove the efficacy and specific killing of selected tumor models, as well as extensive characterization of the models was performed.
Selected xenograft cancer model was earlier used for in vivo efficacy study showing satisfactory tumor growth inhibition. We earlier established this model in a model development studies with identification of expression level, optimal time point for treatment, study duration, potential adverse conditions, take rate and magnitude of effect. We reduce the number of animals used in the study going to the next phase only when the previous is successful. Technicians conduction the study have long experience with similar studies using well refined techniques.