The Power Within: Bifunctional Antibodies Enable Local Tissue Targeting

Despite the many challenges presented by the COVID-19 pandemic, our team at Pandion – like many in the biotechnology sector – has continued our pursuit of new medicines for autoimmune diseases. We are excited to have the opportunity to share some results of our recent experiments, even if virtually, at the 2020 FOCIS meeting this week.

Pandion’s approach to autoimmune disease is to therapeutically mimic the action of intrinsic control mechanisms used by the immune system to re-balance an inappropriate immune response. At the FOCIS meeting, our scientists are sharing preclinical data on therapeutic candidates targeting different control mechanisms. One of which is PD-1, an inhibitory immune checkpoint that is necessary for normal immune homeostasis in humans. Pandion’s posters describe preclinical data demonstrating that our antibodies stimulated PD-1 in order to control active T cell-based immune attack in animal models of autoimmune disease.

Bifunctional antibodies are a distinct approach

The antibodies we are presenting on at FOCIS are bifunctional, which is distinct from the more commonly known format of bispecific antibodies. In contrast to bispecific antibodies in which their Fab sections or “arms” of the Y‑shaped antibody bind two different targets, the effector modules of our bifunctional antibodies bind one therapeutic target. What gives our molecules their second function is the addition of tissue-selective tethers engineered at the Fc portion, or “bottom,” of the antibody. These tissue tethers are designed to allow our antibodies to be precisely delivered to the site of disease where the dysregulated immune attack takes place. Our TALON™ platform gives us the ability to combine an effector module with a tissue-targeted tether module in a bifunctional format or to have the option to leave the tether off, enabling us to create a systemically acting compound.

Our PD-1 agonist work presented at FOCIS shows this effector combined with different tissue tethers for various organs. We believe that localizing the effect of therapeutic molecules to tissues that are the sites of autoimmune and inflammatory diseases is a promising approach and offers the potential for better therapeutic targeting that may lead to improved benefit for patients.

The PD-1 agonist work we are presenting at FOCIS demonstrates that the bifunctional nature of these antibodies can inhibit undesirable immune responses in specific tissues in animal models. I’m happy to share some of the findings from our presentations at the meeting.

Locally targeting the intestine with tissue-tethered PD-1 agonist

Using our TALON platform, we combined our PD-1 agonist with a MAdCAM-1 tether targeting specific tissues in the intestine to modulate activated T cells that cause localized pathology. MAdCAM-1, which stands for mucosal address in cell adhesion molecule 1, is constitutively expressed on endothelial cells in the intestine.

Our data show that our MAdCAM-tethered PD-1 agonist molecule can signal through the PD-1 receptor and inhibit T cell effector functions in vitro. Our data also show that the agonist attenuated intestinal inflammation in a mouse model of graft versus host disease and provided a significant survival advantage compared with vehicle control animals. Analysis of T cell infiltrates into the colon revealed that both CD4+ and CD8+ T cells were decreased in the target tissue. We believe that the ability to locally target the intestine with our bifunctional antibodies provides a potential differentiated approach to treating intestinal autoimmune disease.

Locally targeting the skin with tissue-tethered PD-1 agonist

Skin disorders dominated by pathogenic T cells comprise the largest group of conditions among chronic immune mediated skin diseases. Using our TALON platform, we created bifunctional antibodies that target the skin with different immune effectors. A skin-tethered PD-1 agonist reduced depigmentation in a mouse model of vitiligo by targeting the melanocyte-specific T cells and resident memory T cells. The same approach was used to reduce skin inflammation in a humanized model of imiquimod-induced psoriasis.

Similar to our approach to intestinal disease, we believe that skin-targeted bifunctional antibodies will open important avenues to treat several autoimmune and inflammatory skin conditions with potentially more durable responses.

Soaring ahead

As we reflect on the progress with our pipeline programs in 2020, we are very encouraged by the applications of our TALON platform to create bifunctional antibodies for tissue-targeted immune control. Looking ahead to 2021, we plan to continue to share our data as we continue to advance our modular biologics with the aim to achieve lasting therapeutic outcomes for patients with autoimmune and inflammatory diseases.

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