Dr. Sophie Lucas and Dr. Grégoire de Streel are part of a research team at the de Duve Institute at UC Louvain in Belgium focusing on cancer immunotherapy research. Through their work, they have developed a monoclonal antibody targeting the GARP:TGF-β1 protein complex, in order to selectively block Treg production of the cytokine TGF-β1 and as a result induce anti-tumor activity in mouse models otherwise resistant to anti-PD-1 immunotherapy.
More recently, their research showed that when this antibody is administered in combination with our anti-PD-1 Fc Silent™ antibody to tumor-bearing mice, a significantly higher proportion of mice completely and durably rejected their tumors (de Streel, 2020; Bertrand, 2021).
According to Dr. de Streel, “These data constitute the proof-of-concept that antibody-mediated blockade of GARP:TGF-β1 exerts immune-mediated, anti-tumor activity, opening opportunities for further investigation in clinics.”
Fc Silent™ Antibody Technology
Fc Silent™ represents a genetically engineered Fc domain developed at Absolute Antibody with key point mutations that abrogate binding of Fc receptors (FcγR, FcR), abolishing antibody-dependent cytotoxicity (ADCC) effector function, antibody-dependent cellular phagocytosis (ADCP) and complement-dependement cytotoxicity (CDC). The Fc Silent™ mutation therefore enables researchers to remove effector function in vivo and reduce non-specific background in staining methods.
The RMP1-14 clone is a blocking anti-PD1 antibody, and PD-1 blocking has been one of the main immunotherapy approaches to fight cancer. When the Fc Silent™ mutation is applied to our recombinantly produced syngeneic mouse-anti-mouse anti-PD-1 RMP-14 clone, the antibody has been shown to have even stronger anti-tumor activity than the original non-engineered rat antibody. The UC Louvain researchers decided to use our Fc Silent™ format based on a previous publication (Dahan, 2015) that demonstrated the interest of using a RMP1-14 format that does not bind Fc receptors to block murine PD-1.
Increasing Anti-Tumor Immune Responses
While it is still unclear how the combination of anti-GARP:TGF-β1 and anti-PD-1 [RMP1-14] Fc Silent™ antibodies increases anti-tumor immune response, the researchers propose a few potential mechanisms. “Under its original rat IgG2a format, clone RMP1-14 has high binding affinity for mouse FcgRIIb receptors. It is hypothesized that FcgRIIb could act as a scaffold for PD-1 clustering on the surface of the targeted cell, triggering minimal PD-1 signaling,” according to Dr. de Streel. “Another hypothesis is that engagement of FcgRIIb on myeloid cells could negatively regulate myeloid cells and consequently anti-tumor immunity.”
Future studies may shed light on the mechanism by which this happens. The de Duve Institute research team is currently investigating their anti-GARP:TGF-β1 antibody in combination with our anti-PD-1 Fc Silent™ antibody in other models and projects.
To continue their experiments, the researchers require a reliable source of antibodies. As Dr. de Streel commented on his experience working with Absolute Antibody, “We are looking for high quality products with an affordable price. As we are planning multiple experiments throughout years, we expect to receive products with constant and reproducible qualities among several independent batches ordered.” We’re happy to have delivered on their needs with a reliable antibody.
Excitingly, the team’s findings showing the increased anti-tumor activity in mice have also led to a first-in-human phase I clinical trial in cancer patients. You can stay up to date with Dr. Lucas’s research team and their current findings on their website here.
World Bispecific Summit
2-4th October 2023