Our Approach
Our multi-step approach ensures we select, design and advance the most optimal antibodies for addressing unmet needs and overcoming historic industry hurdles.
Overview
Developing our bispecific antibodies requires a three-step approach:
We utilize a number of design principles to develop our bispecific antibodies, with the main objective of enhancing potency and selectivity. One approach we use is the “Guide x Effector” principle to achieve avidity-driven synthetic specificity. Our team has strong antibody discovery and engineering capabilities, coupled with access to multiple bispecific formats.
The selection of our antibody targets and combination of two bispecific arms are based on our extensive biology and target insights.
We select our programs so that our technology and insights could be harnessed to address specific issues and overcome major historic hurdles in the industry.
Our Design Principles
Bispecific antibodies (bsAbs) have emerged as an important class of therapeutics to address complex diseases. By binding to different antigens – either those on the same cells or two different cells – bsAbs could have effects beyond those produced by monoclonal antibodies. BsAbs that engage and redirect T cells represent a significant percentage of programs in development, including Amgen’s Blincyto®, which was approved in the US for acute lymphoblastic leukemia, and more than 50 programs in various stages of development. Other bsAbs target antigens on the same cell, such as Rybrevant® from J&J. Finally, numerous strategies have been used to development novel bsAb formats (e.g., DART, TandAb, TriTac, among many others).
At Virtuoso, one of the design concepts we use includes pairing a “guide” arm to an “effector” arm. While the effector arm of the bispecific is the main mechanism of action, the guide arm binds to targets with high-expression levels only on target cells. By exploiting this effector/guide concept, we could achieve avidity-driven synthetic specificity to both enhance potency and selectivity.
In a model system of the Wnt/β-catenin signaling pathway, bispecific antibodies based on Virtuoso’s Guide x Effector construct demonstrated striking selectivity (>1,000x) for cells that express the guide antigen.
NK Lee et al. (2018) Cell-type specific potent Wnt signaling blockade by bispecific antibody. Sci Rep 8,766
The Guide x Effector principle is one of many tools we use in designing and developing our bispecifics. Our additional antibody engineering capabilities include:
- Function-guided bispecific format design
- Strong discovery capabilities to ensure species cross-reactivity
- Access to multiple different bispecific formats
- Our antibodies are thoughtfully engineered to maintain high stability, good yield and can use conventional antibody purification and manufacturing processes
Biology & Target Insight
An example of using our biology and target insight to design Virtuoso’s bispecific antibodies is the selection of InterCellular Adhesion Molecules-1 (ICAM-1) as the guide arm for our lead CD38 program.
- ICAM-1 is a type I transmembrane glycoprotein and a ligand for leukocyte integrins aLb2 (LFA-1, CD11a/CD18) and aMb2 (Mac-1, CD11b/CD18)
- ICAM-1 is highly expressed on myeloma, lymphoma and a subset of solid cancers
- There has been previous exploration of ICAM-1’s therapeutic potential in the clinic, but there have not been meaningful clinical results to demonstrate ICAM-1 therapeutic potential.
- We believe pairing CD38 with ICAM-1 could greatly increase potency and efficacy of our bispecific for target tumor cell, especially in those clinical settings where CD38 expression level is low.
Program Selection
In selecting our programs, we prioritize those targets in which a differentiated and improved product profile could be realized by combining our bispecific technology with our biology and target insights. Our lead programs are anti-CD38 and anti-CD47 bispecifics.
CD38
CD38 is an important target found on the surface of mature immune cells, with high expression on plasma cells, other lymphoid and myeloid cells, and some nonhematopoietic cells. It plays varied functions in cancer cells, including promoting growth, survival and adhesion. Recently, the CD38-targetd mAb has become an important treatment in multiple myeloma (MM).
Despite the success of DARZALEX® and SARCLISA®, opportunities exist for next-gen CD38-based therapies:
- MM populations that do not respond to current approved therapies (e.g., patients with low CD38 expression)
- Tumor types in which CD38 could play a role but current approved therapies have yet shown efficacy (e.g., lymphoma)
Virtuoso’s lead program was designed to increase potency and efficacy of our CD38 bispecific in a highly selective manner. We believe this will greatly broaden the clinical application of anti-CD38 therapies.
CD47
The CD47-SIRPα axis is an important part of innate checkpoints that regulates the anti-phagocytic signal for cells. Cancer cells could evade phagocytosis by macrophages by overexpressing CD47. Therapies targeting the CD47-SIRPα axis thus holds tremendous potential for cancer treatments. However, CD47 is also expressed on healthy cells and the anti-phagocytic (or “don’t eat me” signal) is essential for healthy cells’ normal functions. On-target side effects are a major hurdle in fully realizing the potential of anti-CD47 therapies.
Oronsky B., et. al., 2020
Virtuoso has a strategy to overcome shortcomings of current anti-CD47 in clinical development, and our anti-CD47 bispecifics have the potential to achieve the following profile:
- Highly selective targeting of cancer cells
- Incorporation of an IgG1 Fc with full effector function
- Single-agent activities
- Application in both hematological malignancies and solid tumors