Using Bispecific Antibody Reagents to Further Immunotherapy Research

Researchers at the Leiden University Medical Center (LUMC) in the Netherlands are exploring how to use oncolytic viruses to increase the effectiveness of immunotherapy cancer treatments. Immunotherapy, in which a patient’s own immune system is harnessed to fight cancer, has proven effective in targeting hematological cancers but has been less successful for treating patients with solid tumors. The LUMC research team is showing that oncolytic viruses could be used to boost the efficacy of cancer immunotherapy.

Oncolytic viruses are benign viruses with a natural or engineered preference for malignant cells. They selectively infect and replicate in cancer cells, which can kill the cells as well as start an immune response in the tumor microenvironment. This immune response can make an immunotherapy-resistant tumor more susceptible to treatment.

In a new study, published in October 2020 in the Journal for ImmunoTherapy of Cancer, the LUMC researchers used oncolytic reovirus in combination with T-cell-engaging CD3ε-bispecific antibodies to treat cancer in mouse models. The study – led by Thorbald van Hall, professor of tumor immunology, and Nadine van Montfoort, group leader of viro-immunotherapy of cancer – made use of Absolute Antibody’s murine knob-into-hole (KIH) bispecific antibody reagents.

Generating Bispecific Antibody Reagents

Dr. van Hall met Absolute Antibody at a conference while he was searching for a bispecific antibody to target tyrosinase-related protein-1 (TRP-1), a widely used tumor-associated marker. We had recently developed the first commercially available platform to generate fully murine knob-into-hole bispecific antibody reagents. As a result, we were able to generate two bispecific antibody reagents specifically for the LUMC researchers.

Bispecific T-cell engaging antibodies direct the cytotoxic effector function of a T-cell to cancer cells, without the need for specific recognition of the cancer cell by the T-cell.

Both antibodies were bispecific T-cell engagers, with one targeting mouse CD3ε and TPR-1 (TA99), and the other targeting human CD3ε and HER2 (Trastuzumab). To overcome the light-chain pairing problem, the anti-CD3ε binders were converted to single-chain Fvs (scFvs), while adding Absolute Antibody’s proprietary Fc Silent™ mutation to the antibodies abrogated Fc gamma receptor binding without affecting FcRn-mediated recycling.

With these unique antibody reagents in hand, the LUMC researchers designed a study to explore whether oncolytic viruses in combination with CD3ε-bispecific antibodies could improve the immunotherapy treatment of solid cancer tumors.

Activating the Tumor Microenvironment

Both bispecific T-cell engagers and oncolytic viruses are promising cancer therapies, but the new research demonstrates that combining the two approaches could work even better. The researchers first administered oncolytic reovirus to both syngeneic murine and humanized tumor models, then injected the CD3ε-bispecific antibodies. The combined treatment induced strong tumor regression and prolonged survival compared to each treatment option individually.

Preconditioning the tumor microenvironment with oncolytic reovirus resulted in the activation of immunologically cold tumors, explained the researchers. This in turn led to more successful engagement of bispecific antibodies, causing tumor cell death. See the figure below for more details.

 

“Since we found the T cells that entered the tumor after oncolytic virus treatment were virus-specific and not tumor-specific, we needed an original way to use these T cells for tumor killing,” said Dr. van Montfoort. “The bispecific antibodies allowed us to redirect them towards the tumor. Reovirus and bispecific antibodies are a true tumor-killer combo that would not be effective without each other.”

Up next, the researchers hope to move the combination of oncolytic viruses and bispecific antibodies to the clinic. They are now looking to replicate their success using human bispecific antibodies already in the pipeline for immunotherapy treatment of solid cancer tumors.

For more information, read the full text of the new paper or visit the LUMC researchers’ department website.

More information on Absolute Antibody’s bispecific antibodies is available here. Both the anti-CD3ε / TRP-1 bispecific and anti-CD3ε / HER2 bispecific used in the study are available for purchase off-the-shelf in our reagents catalog.