Abstract

Development of antibody drugs against novel targets and pathways offers great opportunities to improve current cancer treatment. We here describe a phenotypic discovery platform enabling efficient identification of therapeutic antibody-target combinations. The platform utilizes primary patient cells throughout the discovery process and includes methods for differential phage display cell panning, high-throughput cell-based specificity screening, phenotypic in vitro screening, target deconvolution, and confirmatory in vivo screening. In this study the platform was applied on cancer cells from patients with Chronic Lymphocytic Leukemia resulting in discovery of antibodies with improved cytotoxicity in vitro compared to the standard of care, the CD20-specific monoclonal antibody rituximab. Isolated antibodies were found to target six different receptors on Chronic Lymphocytic Leukemia cells; CD21, CD23, CD32, CD72, CD200, and HLA-DR of which CD32, CD200, and HLA-DR appeared as the most potent targets for antibody-based cytotoxicity treatment. Enhanced antibody efficacy was confirmed in vivo using a patient-derived xenograft model.

Details

Title
A platform for phenotypic discovery of therapeutic antibodies and targets applied on Chronic Lymphocytic Leukemia
Author
Ljungars, A 1 ; Mårtensson, L 2 ; Mattsson, J 2 ; Kovacek, M 2 ; Sundberg, A 3 ; U-C, Tornberg 2 ; Jansson, B 4 ; Persson, N 2 ; Kuci, Emruli V 5 ; Ek S 5 ; Jerkeman, M 6   VIAFID ORCID Logo  ; Hansson, M 6   VIAFID ORCID Logo  ; Juliusson, G 6 ; Ohlin, M 5 ; Frendéus, B 2 ; Teige, I 2 ; Mattsson, M 2 

1  BioInvent International AB, Lund, Sweden (GRID:grid.431908.7); Lund University, Department of Immunotechnology, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361) 
2  BioInvent International AB, Lund, Sweden (GRID:grid.431908.7) 
3  BioInvent International AB, Lund, Sweden (GRID:grid.431908.7); HansaMedical AB, Lund, Sweden (GRID:grid.431908.7) 
4  BioInvent International AB, Lund, Sweden (GRID:grid.431908.7); Lund University, Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361) 
5  Lund University, Department of Immunotechnology, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361) 
6  Skåne University Hospital, Lund University, Hematology clinic, Lund, Sweden (GRID:grid.4514.4) 
Publication year
2018
Publication date
2018
Publisher
Nature Publishing Group
ISSN
2397768X
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41698-018-0061-2
ProQuest document ID
2389706822
Copyright
© The Author(s) 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.