Antibody Engineering 2013: Tuesday's Sessions

On Tuesday, sessions focused on The Interface between Monoclonal Antibody Therapy and Cellular Immunity in Cancer.  In the session titled Immunotherapy-induced Antibodies, Glenn Dranoff, M.D., Professor of Medicine of the Dana Farber Cancer Institute pointed out that most human tumors have over 100 coding sequences. Tumors have many features of healthy tissues which lead to immune tolerance. Opportunities for immunotherapy: vaccines, t cell modulation and tumor microenvironment. The immune system has a long term memory. Lung cancer is a good target for immunotherapy. He also brought this webpage to our audience's attention: Cancer Immunology Research.

In the session Changing Tumor Microenvironment by Local Radiation and Modified Antibody, Yang-Xin Fu, M.D., Ph.D., Professor, Department of Pathology, The University of Chicago shared what he sees as the major barriers in immunotherapy:

• -Difficult to break tolerance
• -Poor recruitment to tumor site
• -Strong suppressive environment within the tumor site
• -Fast growing tumor in mouse model
• -Lack of defined antigens and adjuvantn for vaccination and T cell transfer. This means no clear defined antigens in many patients.

In the next session from K. Dane Wittrup, Ph.D., C.P. Dubbs Professor of Chemical Engineering and Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology titled Coordinated Tumor Growth Suppression via Synergistic Innate and Adaptive Immunotherapy, he shared a little bit on why tumor resistance is inevitable. Cancer is adapting, and you’re racing to stay ahead of it. For the most part, anti-tumor antibodies approved are chosen because of their activity in cell culture assays. The bridge to the immune system and adaptive response may be the future of cancer therapies.

Afternoon sessions started off reflecting on the contributions of two great men lost to the field this past year - Pim Stemmer and Michael Neuberger.  Volker Schellenberger, Ph.D., CEO, Amunix then looked farther into XTEN – A Protein Polymer for Half-Life Extension and Drug Conjugation.  XTEN Concept includes the defined length, defined sequence, 3-7 monomers and a random configuration. It rings the precision of recombinant production of polymers. Drug targeting linker is the increased drug load, utilize Ab fragments, peptides and metabolites; extremely hydrophobic, reduced non-specific technology and improved purity

Our next presentation, Innovation by Recombination was delivered by Frances Arnold, Ph.D., Dickinson Professor, Chemical Engineering,Bioengineering and Chemistry, California Institute of Technology.    Here first question we spoke to was "How do we compose new enzymes?"  It’s difficult - enzyme families are the productions of millions of years of mutation and natural selection. Looking at the natural world is the place to start. Humans have been modifying the biological world for ages. The technology from recombinant DNA evolution technology has given us a new set of tools. Directed evolution exploits smooth paths in the fitness landscape – control the mutations and the rate at which they’re made. Making DNA sequences is easy but how will it work when you put it into different cells?

Enzymes and other proteins are highly evolvable. Biology is full of details and they matter. It’s hard to catch nature in the act of evolution. We don’t know when the new enzyme activities came about but we know the features. Nature can adapt to new niches. For evolution to happen, it must be close to something you already have.

Andreas Plückthun, Ph.D., Professor of Biochemistry, University of Zurich, Switzerland, in his presentation Directed Evolution of Stable GPCRs for Use as Targets and for Structure Determination, shared the reasons we need stable receptors?

• - Drug screening – all small molecule screening for CPCRs is cell-based, screening of therapeutic antibodies and other binding molecules
• - Structural understanding
• - Get around experimentation by computation alone

In the presentation Continuous Directed Evolution of Proteins, David R. Liu, Ph.D., Professor of Chemistry and Chemical Biology, Howard Hughes Medical Institute Investigator, Harvard University looked at the many ways to evolve lab proteins: Translation, selection, replication, and mutation.

What is needed for this to happen?  They set out to develop a system to perform mutation, selection and replication in a continuous, self-sustaining manner that requires no human intervention

• -fast enough to support many rounds of evolution per day
• -self-sustaining (no transformation or screening)
• -general for a variety of protein and nucleic acid activities
• -resistant to error catastrophe and takeover by “cheaters”

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