Challenges Still Abound in Antibody Therapeutics

Andrew Scott, MB, BS, MD

Ludwig Institute for Cancer Research Centre for PET, Austin Hospital

Melbourne, Australia

The laboratory program that Andrew Scott, MB,BS, MD, heads at the Ludwig Institute for Cancer Research in Australia is focused on the development of recombinant antibodies for diagnostic and therapeutic application in tumors. Its work has led to the successful translation of novel potential cancer therapeutics into clinical development.

1

How have antibodies changed the landscape of anticancer therapy?

2

In your opinion, what has been the most significant anticancer antibody success story?

3

What are the most significant questions relating to antibodies as anticancer therapy?

4

Thus far, the clinical successes with antibodies have been in combining them with other agents. Do you think they have potential as single agents?

5

What is the most recent promising development in antibody engineering?

Over the last decade, antibodies have emerged as one of the most successful therapeutic approaches in cancer therapy. This is due to the specificity of antibodies for targets relevant to cancer biology and immune regulation, the array of functional effects that can be deployed, and the broad range of tumor types that can be treated. Importantly, the interface of academia (where target discovery and/or initial antibody generation often occurs) and pharmaceutical development programs is particularly relevant to antibodies, and this approach is now pursued in developing many new anticancer therapeutics.The approval of trastuzumab for the treatment of HER2-positive breast cancer was instrumental in establishing antibody therapeutics as a major strategy in cancer treatment, as it was the first antibody to be approved in solid tumors, and in addition, it was one of the first examples of personalized medicine due to the identification of HER2 expression in tumors being predictive of response.A key challenge for antibody therapies in cancer is the selection of new targets, due to the broad array of potential options and the complexity of validation. Resistance mechanisms, in part due to plasticity of tumor cell signaling and variable phenotype, are a major focus of antibody research and have a significant impact on designing optimal combination therapeutic strategies. The excitement surrounding new antibody formats (eg, bispecifics) is still to be confirmed by response rates in clinical trials. Finally, the cost of antibody therapeutics is a major limitation to access for many cancer patients, and is a challenging issue worldwide.One of the major challenges in cancer therapy is that resistance mechanisms will impact on clinical efficacy and duration of response. Antibodies may act by multiple mechanisms, including abrogating cancer cell signaling, activation of immune cells, and inhibition of vascular growth in tumors, all of which may have significant efficacy, but escape mechanisms may blunt response. Combining antibodies with chemotherapy, kinase inhibitors, or other antibodies is therefore a logical strategy to achieve optimal therapeutic effect. As single agents, antibodies have shown significant responses when targeting immune checkpoints (eg, ipilimumab), although recent clinical trial data indicate that multiple immune checkpoints blocked by antibodies (eg, CTLA-4 and PD-1) may have markedly improved therapeutic effect, as highlighted at this year’s ASCO [American Society of Clinical Oncology] meeting. The use of antibodies as single agents for payload delivery (eg, antibody-drug conjugates, or isotopes) is an area where remarkable clinical success has been seen, particularly in Hodgkin and non-Hodgkin lymphoma, and in breast cancer, with new antibody-drug conjugates showing great promise in phase I/II trials.Technologies for generating human antibodies have made great advances over the last five years, and provide multiple strategies for generating unique antibody constructs. Amongst the most promising new areas in antibody engineering is bispecific antibody formats, where multiple targets can be engaged and activated (or inhibited) by the same antibody.