At the American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, on Tuesday 4th April, a poster session titled “BITES Bispecifics and Checkpoints” took place.
One of the posters on display (3631 / 4) was titled “Delivery of a CD20 transferrin receptor VNAR bispecific antibody to the brain for CNS lymphoma” by Frank S. Walsh from Ossianix, Philadelphia, PA, and colleagues.
Currently, the challenge facing the development of biologic therapies for CNS-related cancers is getting the agent to cross the blood brain barrier.
This group used in vitro and in vivo phage display technology; they identified a panel of cross species (rodent, primate, and human) binders to the Transferrin Receptor 1 (TfR1) from synthetic libraries of shark Variable Antigen Receptors (VNARs).
- To begin with, the anti-TfR1 VNARs were attached to an Ig Fc backbone for testing in mice
- When therapeutic doses (2mg/kg) were administered via tail vein injection, high levels of VNAR-Fc antibodies were reported in the brain after 18 hours, >5% of the plasma levels
- Brain fractionation studies indicated that VNAR-Fc antibodies to TfR1 translocated to the brain parenchyma and were not retained in capillaries
- The lead anti-TfR1 VNAR was used to target aberrant B-cells in the brain for diseases like cerebral Lymphoma
- A family of anti-CD20/TfR1 bispecific molecules were produced; small VNAR were linked to either the N- and C- terminus of heavy and light chains to generate monovalent and bivalent fusions
- The anti-CD20 agent used was rituximab
- 18 hours after dosing at 3.75mg/kg, ≥4 different formats gave outstanding brain penetration
- Unmodified rituximab brain plasma ratio = 0.25; the best anti-TfR1-rituximab bispecific formats = between 2 to 5%
- The bispecific formats maintain Antibody-Dependent Cell Cytotoxicity (ADCC)
The poster concluded by stating that these bispecific formats will be investigated further for brain penetration in non-human primates and in CNS Lymphoma rodent models.
If these results are successfully replicated in larger animals, the delivery of the bispecific CD20/TfR1 antibody would present as a safer and more effective substitute to intrathecal delivery of CD20 antibody and could have wide range of uses to treat and manage B-cell driven brain cancers.