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Andreas Plückthun, PhD
KEYNOTE: Protein Engineering To Extend The Binding Protein Paradigms
University of Zurich
H.Kaspar Binz, Ph.D.
Stronger Than Ever – Past, Present, and Future of Novel Scaffold Drugs
Molecular Partners AG
- Design strategies
for creating binding protein scaffolds
- Beyond conventional applications
- A novel strategy to create modular binding proteins
The 2018 chemistry Nobel laureates’ work paved the way for the use of non-antibody binding proteins in drug development. It was while turning the academic ideas into businesses, when the differentiating strengths of novel scaffolds crystallized. With safety doubts dispelled with clinical data, we now start to see the technologies to unfold their key strengths.
Affimer therapeutics are based on the human protein Stefin A, a small (12kDa) intracellular protease inhibitor. We have built large phage display libraries (1x1010), generating Affimer binders to range of therapeutically relevant targets (e.g. PD-L1, LAG-3). We have shown that the Affimer scaffold can be formatted as in-line, Fc or antibody fusions to create bispecific molecules are able to engage both target antigens.
ALG.APV-527 is a novel 4-1BB x 5T4 targeting bispecific antibody that induces potent CD8 T cell activation only when engaged by 5T4, a tumor associated antigen. The binding domains of ALG.APV-527 were isolated from the ALLIGATOR-GOLD® human scFv library (Alligator Bioscience AB), then optimized and developed for use in the bispecific ADAPTIR Next Generation format (Aptevo Therapeutics Inc.).
Multi-specific antibodies have the unique ability to elicit an immune response at the site of a tumor. By minimizing the toxicities associated with a systemic immune response, tumor targeted multi-specific antibodies can increase the therapeutic index for new immune activating cancer therapies. Using a unique sequence-based discovery approach along with proprietary transgenic rats, we have created a large collection of fully human antibodies targeting a variety of tumor antigens and activating receptors on immune cells. Our novel discovery platform combines antibody repertoire deep sequencing, high-throughput gene assembly, and recombinant expression. Using machine learning tools, we are able to rapidly establish sequence-activity relationships and identify key residues and variable region positions in the antibody repertoire that had desired agonist behavior. As one example, we have created a panel of aCD3:aBCMA bispecific antibodies for the treatment of multiple myeloma that stimulate different levels of T-cell activity. These bispecific antibodies exhibit a spectrum of in vitro tumor cell killing activity with varied levels of cytokine release. In summary, we have created a platform for tunable immune activation at the site of the tumor that works with a variety of tumor antigens.
Creating lymphocyte activating drugs from natural cytokines has proven challenging due to their high potency, low tolerability, and fast clearance, which limits therapeutic index. Xencor has developed several cytokine-Fc fusions using our engineered heterodimeric antibody Fc domain. Each molecule has been precisely tuned for potency and/or selectivity to allow higher dose levels and provide more sustained exposure.
T-cell engagers are potent molecules capable of killing cells expressing the target at low levels. HER2 is an important target overexpressed in many tumor but also expressed in normal tissue. We describe the development of T-cell engager based on a low affinity anti-Her2 antibody with a big avidity component that is more selective than a traditional IgG-like antibody format in killing tumor cells.
Monoclonal antibodies (mAbs) against the envelope glycoprotein represent a promising therapeutic platform for managing filovirus infections. However, mAbs that exhibit neutralization or protective properties against multiple filoviruses are rare. Here, we examined a panel of engineered bi- and trispecific antibodies, whereby variable fragments of mAbs that target epitopes from multiple filoviruses were combined, for their capacity to neutralize viral infection across filovirus species. We found that bispecific combinations targeting EBOV and Sudan virus (SUDV, another ebolavirus), provide potent cross-neutralization and protection in mice. Furthermore, trispecific combinations, targeting EBOV, SUDV, and MARV, exhibited strong neutralization potential against all three viruses. These results provide important insight into multispecific antibody engineering against filoviruses and will inform future immunotherapeutic discovery.
The following case studies covering rationale, molecular design, preclinical validation and clinical experience to date will be presented: (A) Application of Fc-engineering to optimize effector function of anti-HER2 mAb therapy; (B) Utilization of bi-specific bivalent DART® molecules to direct T-cell lysis of tumor cells and (C) Utilization of bi-specific tetravalent DART® molecules to simultaneously blockade two checkpoint pathways.