Agenta's Novel Approach

The Next Generation of Checkpoint Inhibitors

When cancer cells progress, sialic acid expression on those cells are often unregulated. This is one mechanism cancer cells use to hide from the immune system. Sialic acids are commonly part of glycoproteins and glycolipids, where they decorate the end of sugar chains at the surface of cells or soluble proteins.

Sialylated glycans are recognized by Siglec (sialic acid-binding immunoglobulin-type lectins) receptors, which are expressed on the surface of both innate and adaptive immune cells. Hypersialylation of glycans is linked to increased immune evasion, drug resistance, tumor invasiveness, and metastasis.

Although there are 15 different Siglecs present in humans, the inhibitory Siglecs most strongly implicated in immune evasion of cancer cells are Siglec-7 and Siglec-9, which are expressed on NK cells, macrophages, and T cells. AGENTA is developing first-in-class monoclonal and bi-specific antibodies which block Siglec-7 and Siglec-9 inhibitory receptors to kill cancer cells with both NK and T cells. AGENTA is also applying its proprietary platform to generate bispecific and trispecific antibody engager products to kill cancer cells.

AGENTA and its collaborators at the Wistar Institute extensively utilize artificial intelligence (AI) and machine learning methods in silico to model antibody and antigen interactions in the computer. Such methods dramatically accelerate the time to select the optimal candidates for in vivo testing and provides AGENTA with a significant R&D advantage.

The Problems and Opportunities

In recent years, several T cell-focused immunotherapy products, including PD-1/PD-L1 immune checkpoint inhibitors (such as KEYTRUDA® and OPDIVO®), have dramatically improved cancer therapies.

While considered highly successful, the currently approved immune checkpoint inhibitors work in less than 20% of patients in most cancers. For instance, PD-1/PD-L1 inhibitors are effective in only 4 to 15% of ovarian cancer patients

The AGENTA Solution

The Problems and Opportunities

AGENTA’s Siglec-7 and Siglec-9-targeted immune checkpoint inhibitors could improve overall cancer treatment effects by activating both NK cells and T cells.

First-in-class immune checkpoint inhibitor AGT-110 activates NK cells and T cells to kill cancer cells by reversing the immune “OFF” switch to an “ON” position by blocking Siglec-7 receptors.

AGENTA plans to develop these therapies as stand-alone products as well as in combination with approved PD-1/PD-L1 immune checkpoint inhibitors. Because Siglec-7 or Siglec-9 pathways are distinct from the PD-1/PDL-1 pathways, it is believed that AGENTA’s drug candidates could work synergistically with approved PD-1/PD-L1 immune checkpoint inhibitors. Preclinical data supports this approach.

The Opportunity

The global immune checkpoint inhibitors market size is estimated at $50.28 billion in 2024 and is anticipated to reach around $229.60 billion by 2034, expanding at a CAGR of 16.40% from 2024 to 2034.

Each approved immune checkpoint inhibitor represents potential multi-billion dollar revenues. Top selling PD-1 checkpoint inhibitor product, KEYTRUDA®*, generated $29.5 billion in revenue in 2024. OPDIVO®* generated $9.3 billion in revenue in 2024.

PD-1/PD-L1 therapy patents are set to expire in 2028.

AGT-110: Anti-Siglec-7 Monoclonal Antibody

• In preclinical studies, AGT-110 (anti-Siglec-7 mAb) showed the ability to kill BRCA2-mutated and PARP–resistant PEO4 ovarian cancer cells in xCELLigence-based in vitro killing assays.

•The potency of AGT-110 was greater than KEYTRUDA (anti–PD-1 mAb).

•The combination of AGT-110 and KEYTRUDA showed significant enhancement of PEO4 cell killing.

Read more in the peer-reviewed research article:

Bordoloi et al., Sci Adv,. 2023. DOI: 10.1126/sciadv.adh4379

https://www.science.org/doi/10.1126/sciadv.adh4379

AGT-210: Bi-Specific Antibody NK Cell Engager

AGENTA is also applying its technology to bi-specific antibody engagers, which simultaneously bind to an antigen on tumor cells and a surface molecule on NK cells and T cells to induce tumor killing.

AGT-210 is a bi-specific antibody which directly fuses the Siglec-7 reactive binding site of the Siglec-7 mAb to a second mAb that uniquely binds to an ovarian cancer antigen named Follicle Stimulating Hormone receptor (FSHR). In both bench and humanized mouse model challenge studies, AGT-210 was effective at targeting ovarian cancer, activating NK cells in local proximity and efficiently killing multiple ovarian cancer cell lines.

Read more in the peer-reviewed research article:

Bordoloi et al., Sci Adv,. 2023. DOI: 10.1126/sciadv.adh4379

https://www.science.org/doi/10.1126/sciadv.adh4379

FAQs

What are T cells?

T cells are a vital part of the human immune system — specialized white blood cells that play a key role in identifying and eliminating harmful threats like viruses, bacteria, and cancer cells. Often described as the "command and control" center of the immune response, T cells help coordinate how the body reacts to disease and are capable of directly killing infected or abnormal cells.

What are Natural Killer (NK) cells?

Natural killer (NK) cells are a powerful part of the body’s frontline immune defense. Another type of white blood cell, NK cells are designed to act quickly — identifying and destroying cells that are infected with viruses or have become cancerous, often before the rest of the immune system has even mobilized.

Unlike T cells, which require activation and training to target specific threats, NK cells work immediately and without prior exposure, making them a critical part of the body’s innate immune system.

What sets NK cells apart:

Fast, autonomous response to abnormal cells
Ability to target a broad range of threats without needing prior recognition
Natural role in controlling early stages of cancer and viral infections

What are checkpoint inhibitors?

Checkpoint inhibitors are a groundbreaking class of immunotherapy drugs that help the body’s immune system recognize and attack cancer more effectively.

Normally, immune cells like T cells have built-in “checkpoints” — safety mechanisms that prevent them from attacking healthy cells. However, many cancer cells exploit these checkpoints to hide from the immune system and avoid being destroyed.

Checkpoint inhibitors are designed to block these "off switches", effectively releasing the brakes on the immune system and allowing T cells to recognize and eliminate cancer cells.

Key checkpoints commonly targeted by these therapies include:

PD-1 / PD-L1: Inhibiting this pathway helps T cells detect and attack tumors.
CTLA-4: Blocking this checkpoint enhances T cell activation at an earlier stage.

What are Siglecs?

Siglecs (short for Sialic acid-binding immunoglobulin-like lectins) are a family of cell surface receptors found mainly on immune cells, including natural killer (NK) cells, macrophages, and certain types of T cells. They play a crucial role in regulating immune responses by recognizing specific sugar molecules — called sialic acids — that are present on the surface of many cells in the body.

Similar to the PD-1/PD-L1 pathway, Siglecs act like immune system “brakes.” When they bind to specific sugars (called sialic acids) found on cell surfaces — especially on cancer cells — they send a signal that dampens the immune response, effectively telling NK cells to stand down. Many tumors exploit this mechanism by covering themselves in these sugars to avoid being attacked.

Agenta's Novel Approach

The Next Generation of Checkpoint Inhibitors

The Problems and Opportunities

The Problems and Opportunities

The Problems and Opportunities

The AGENTA Solution

The Problems and Opportunities

The Problems and Opportunities

The Opportunity

AGT-110: Anti-Siglec-7 Monoclonal Antibody

AGT-210: Bi-Specific Antibody NK Cell Engager

FAQs

What are T cells?

What are Natural Killer (NK) cells?

What are checkpoint inhibitors?

What are Siglecs?

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