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Keynote Presentation: From Antibodies to Synthetic Proteins
University of Toronto
Martin Steegmaier, Ph.D.
From Format to Function - Engineering Transformative Antibody Therapeutics
Roche Innovation Center Munich
Next Generation Protein Therapeutics - Latest Developments
Synthetic antibodies enable applications beyond the reach of natural antibodies. Moreover, alternative scaffolds such as ubiquitin can be used to modulate proteins in live cells. In addition, small scaffolds that function like antibodies but are amenable to full chemical synthesis enable D-protein engineering. In sum, these advances greatly extend the applications of protein engineering in biological research and therapeutic development.
We use natural ligands and receptors as scaffolds for protein engineering to leverage their inherent biophysical and biochemical properties. I will present our recent data on new therapeutic candidates engineered to possess high affinity and unique specificity for applications in oncology.
New Technologies for Design and Discovery of Next Generation Protein Therapeutics
In this talk, I will describe library design, selection strategies, and data analysis using next generation sequencing (NGS) for discovery of biologic leads.
Creative Engineering and Design Approaches for Next Generation Protein Therapeutics
Bi- and multi specific antibodies enable the exploration of new biological concepts and treatment strategies. Within Roche such next generation biologics have found broad application prospects in onco-immunological and anti-inflammatory approaches. But their use goes far beyond these established applications to convey unique mode of actions.
Integrated platforms can be used to mitigate immunogenicity risk and characterize immune responses during the drug design and development stages. ProImmune offers mutational activity mapping for optimal protein design, DC-T/T cell proliferation assays for biologic lead selection/optimization, a Mass Spectrometry assay for characterization of antigen presentation; HLA-peptide binding assays to characterize individual epitopes & undiluted whole blood cytokine storm assays.
Using transgenic rats and a unique discovery approach, we have created a large collection of fully human anti-CD3 antibodies with diverse T-cell agonist activities. Our novel discovery platform combines antibody repertoire deep sequencing, high-throughput gene assembly, and recombinant expression and allows us to identify antibodies with finely tuned functional activities. The collection of CD3 antibodies identified by our platform show diverse in vitro T-cell activation profiles measured by CD69 upregulation, IL2, and IFNg production. Using our discovery platform, we have also generated human domain antibodies targeting tumor antigens that may be combined with our unique CD3 antibodies to create multi-specific molecules that mediate redirected T-cell killing of tumor cells. As one example, we have created a CD3xBCMA bispecific antibody (TNB-383B) for the treatment of multiple myeloma. TNB-383B kills multiple myeloma cells in vitro and in vivo in a BCMA-dependent manner, and kills primary patient myeloma cells ex vivo. Futhermore, TNB-383B induces significantly reduced cytokine secretion by T-cells without reduction of efficacy in vivo or ex vivo. In summary, we have created a novel T-cell engaging bispecific antibody platform with tunable T-cell agonism that can be used to optimize the therapeutic index for a variety of tumor antigens.
We have developed a novel bispecific antibody that binds to two distinct epitopes on MET. The METxMET bispecific antibody blocks HGF binding and exhibits very low agonist activity Furthermore, the METxMET bispecific antibody effectively promotes MET degradation, thereby inhibiting ligand-independent signaling in MET-amplified tumor cells. The METxMET bispecific antibody exhibits strong anti-tumor efficacy in xenograft models harboring MET genetic alterations.
ATOR-1015 is a CTLA-4 x OX40 bispecific immune activating antibody developed for tumor-directed immunotherapy. ATOR-1015 binds both targets simultaneously, promoting cell-cell interactions expected to enhance the immuno-stimulating effect of the compound. The mode of action of ATOR-1015 is thought to be a combination of regulatory T cell (Treg) depletion and effector T cell activation. It can be seen as a next generation CTLA-4 antibody with tumor-directed activity and augmented Treg depletion.
ATOR-1015 is currently in pre-clinical development and clinical trials will start in the second half of 2018.
Inhibrx’s modular single domain antibody platform enables crafting of differentiated biotherapeutics with functionalities beyond what is achievable with conventional antibodies. Therapeutic formats include multivalent and multispecific therapeutics to appropriately interface with the biology of each target antigen. These biotherapeutics can be designed for enhanced signaling, antigen-dependent agonism and specific immune cell recruitment and activation.