Title: Next generation antibody-drug conjugates for cancer therapy
Funder: Cancer Research UK

Abstract: BACKGROUND This study represents a request for funding of a collaboration between the lead applicant, an antibody engineer, and joint lead applicant, Raimund Ober, who is a bioengineer. We have run a joint laboratory for over 15 years that has to date resulted in over 60 peer-reviewed publications. We are planning to relocate from Texas to the new Centre for Cancer Immunology (CCI) at the University of Southampton in late summer 2017, and seek funds to continue and considerably extend an existing project related to the generation of antibody-drug conjugates (ADCs) with improved efficacy. This project is currently supported by the Cancer Prevention and Research Institute of Texas and cannot be transferred. We believe that the CCI, with its strength in both basic science and translational work, provides an excellent environment for our planned studies. AIMS These studies have two goals: first, to develop highly efficacious ‘next generation’ ADCs and second, to use fluorescence microscopy to gain novel mechanistic insight concerning the subcellular trafficking behavior of these therapeutics and their targets that will define the ground rules for the production of superior ADCs. METHODS The project involves the production of next generation ADCs targeting HER2, CD19 and CD22 using a combination of antibody engineering, subcellular trafficking analyses using advanced fluorescence microscopy and testing as therapeutics in mouse xenograft models. Sally Ward has extensive experience in antibody/protein engineering, cellular trafficking studies and mouse models, and Raimund Ober is an expert in fluorescence microscopy including single molecule and multifocal plane imaging. The aspects of these analyses involving the targeting of hematopoietic malignancies will be carried out in close collaboration with CCI members. Our proposed study therefore involves the confluence of several different expertises to develop next generation ADCs for cancer therapy. HOW WILL THE RESULTS BE USED? The scientific results of this project are expected to lead to the mechanistic understanding, at the level of subcellular trafficking behavior, of ADCs that will contribute to their effective design for multiple different tumor targets. We also expect to generate ADCs for specific targets that will be translated to the clinic following established pathways that we and our collaborators at the University of Southampton have used in the past.

Lay abstract: BACKGROUND Although the use of antibody-drug conjugates (ADCs) to treat cancer represents an exciting and rapidly expanding area, concerns about toxicities remain. The current research program is directed towards developing a new class of ‘next generation’ ADCs that are effective at lower doses and have reduced toxicities. This study represents a request for funding of an interdisciplinary collaboration between the principal investigator (PI), an antibody engineer, and the co-PI who is a bioengineer. The research will be carried out in the new Centre for Cancer Immunology (CCI) at the University of Southampton. We believe that the CCI, with its strength in both basic science and translational work, provides an excellent environment for the planned studies. AIMS These studies have two goals: first, to develop highly efficacious ‘next generation’ ADCs and second, to use fluorescence microscopy to gain novel mechanistic insight concerning the subcellular trafficking behavior of these therapeutics and their targets that will define the ground rules for the production of superior ADCs. METHODS The project involves the production of next generation ADCs using a combination of antibody engineering, subcellular trafficking analyses using advanced fluorescence microscopy and testing as therapeutics in mouse xenograft models. The PI, Sally Ward, has extensive experience in antibody/protein engineering, cellular trafficking studies and mouse models, and Raimund Ober (co-PI) is an expert in fluorescence microscopy including single molecule and multifocal plane imaging. The aspects of the proposed analyses involving the targeting of hematopoietic malignancies will be carried out in close collaboration with CCI members. Our proposed study therefore involves the confluence of several different expertises to develop next generation ADCs for cancer therapy. HOW WILL THE RESULTS BE USED? The scientific results of this project are expected to lead to the mechanistic understanding, at the level of subcellular trafficking behavior, of ADCs that will contribute to their effective design for multiple different tumor targets. We also expect to generate ADCs for specific targets that will be translated to the clinic following established pathways that we and our collaborators at the University of Southampton have used in the past.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS