Vision, leading antibody innovation
Modern science demands vision. We’ve been shaping biotechnology innovation for nearly three decades, leading the industry in antibody drug development through core technologies that include hybridoma and phage display. We’ve also mastered optimization to improve the safety and potency of antibody leads. We anticipate the future; we follow the science that translates into successful antibody therapeutics.
Isolating the lead Antibody
Hybridomas and the antibodies they produce are uniquely efficient. Starting with the immunization of a mouse with a target of interest, we immortalize antibody-producing B cells by fusion with myeloma cells. These generate the hybridomas that produce stable monoclonal antibodies (mAbs).
A robust phage display library can identify hundreds of potential drug candidates to target proteins. Our technique exploits a biological characteristic of a bacterial virus that expresses foreign proteins on its surface.
Displaying the amazing immune system on the surface of phage is the starting point for the majority of our drug development projects. Within our proprietary antibody libraries lies the discovery of novel therapies—including the ability to identify large numbers of diverse antibodies for our most challenging targets.
Optimizing the lead Antibody
Decreasing an antibody’s lead immunogenicity potential is crucial. Humanization or germlining-merging an antibody’s complementary determining regions (CDRs) with human frameworks-minimizes non-human amino acids in the final molecule. Our proprietary “framework shuffling” platform also allows us to select for characteristics such as affinity, expression and stability.
Humanization / Germlining
Humanization—merging an antibody’s complementary determining regions (CDRs) with human frameworks — and germlining – mutating select non-human frameworks amino acid to human residues - minimize non-human amino acids in the final molecule. Our proprietary “framework shuffling” platform also allows us to select for characteristics such as affinity, expression and stability.
Optimizing the lead antibody often requires increasing the binding affinity to its cognate antigen. We do this through affinity maturation using various platforms that include phage display, phase expression or ribosome display. Ribosome displays, in particular, allow access to unprecedentedly large protein libraries.
We can also introduce various function-altering mutations into the lead antibody. In particular, these types of modifications can either increase or decrease antibody-dependent cell-mediated cytotoxicity (ADCC) activity. This can enhance the potency of a lead antibody toward select targets, as well as its safety profile.
Structural biology is essential to understanding an antibody’s mechanism of action, functional or biophysical properties, and potential future strategies for lead optimization. Our three primary approaches include epitope mapping, X-ray crystallography and computational modeling—a powerful combination toward precision medicine.
Antibody Drug Conjugates
Our proprietary ADC payload and technology—based on site-selective conjugation—is driving an emerging preclinical pipeline of projects. While oncology is an area that benefits from ADC, we also are exploring ways to use this technology across other therapeutic areas. This includes linking peptides and small molecules of interest to therapeutic antibodies so that we can enhance their efficacy.
Behind the unique security system that is the blood-brain barrier (BBB) are well-validated targets to which we need access. We have developed and deployed a number of transporter molecules; fused to a biologic, these molecules cross the BBB and provoke a central pharmacology response. We are using this platform preclinically to develop antibody and peptide-based therapeutics for several indications.
The Power of Numbers
An individual molecule that can target two or more disease-associated antigens across therapeutic areas is powerful. We create these multispecific antibodies with genetic engineering technology that maintains favorable biochemical and biophysical properties, and can be produced in mammalian cells with high yields.
Nanoparticles have the unique ability to accumulate around tumor tissue. But, this enhanced permeability and retention (EPR) effect varies within cancer type and patient population. Our scientists are looking at ways to design targeted nanoparticles and nanomedicines that enhance cancer therapies.
Small Package, Big Returns
Smaller molecular weight-binding scaffold technologies give us alternatives to antibodies as binding molecules. These are based on the fibronectin type III (Fn3) domain of tenascin (Tn3), which expresses well in E. coli and has been engineered for high stability. Tn3 has three loops that we can randomize for tailor binding to various targets and is suited to fusion for generating multimeric or multispecific constructs.
Directed Tumor Death
Oncolytic viruses are selective and infectious—and perhaps one of the most potentially precise ways we may have to attack tumor cells. The process is highly immunogenic, leading to direct and immune-mediated tumor cell destruction, localized production of therapeutic transgenes, and immune cell activation.
Phenotypic Selections and Screenings
We are perpetual miners. Most drug hunting is targeted, but we have a team that constantly searches our multiple libraries on primary cells. In each therapeutic area, our team is looking for not only binders against these cells, but functional molecules in relevant secondary assays. When we find something interesting, we use proteomics to identify the target antigen and fast-track the molecule into our portfolio.
A Unique Approach
Our therapeutic peptide approach is unique in the industry. Along with the strong integration of synthetic and recombinant expression expertise, our in-house capabilities include peptide design, formulation and delivery. We work with known and novel incretins, and have also invested in cyclic peptide approaches for intracellular protein-protein interactions.
Big Data Biotech
Getting to answers quickly often means sorting through hundreds of phenotypes. Tissue phenomics allows us to mine these data faster and more precisely. This helps us to discover, develop and validate new biomarkers, design better clinical trials, and improve patient stratification and decision making.