Introduction of Vonlerolizumab

Vonlerolizumab is a humanized agonistic monoclonal antibody that stimulates the OX40 receptor (CD134) on T cells. Through stimulating the immune system's own natural defenses against and destruction of tumor cells, vonlerolizumab promises to revolutionize the success of cancer therapies, particularly when paired with other immune-modulating therapies. Vonlerolizumab also has a distinctive mechanism of action that sets it apart from other immunotherapies. Vonlerolizumab works not directly against the tumor cells as antibodies do, because vonlerolizumab works primarily on immune cells—specifically, it activates T cells, increasing their propensity to recognize and attack cancer cells. Not only does this increase the immune response, but it also decreases the anti-inflammatory effect of regulatory T cells (Tregs) that are sometimes used to evade immune attacks by tumors. Creative Biolabs is taking serious steps to help with new immunotherapies, such as the research into antibodies such as vonlerolizumab. With the latest technologies and intimate knowledge of immune biology, Creative Biolabs is working to develop treatments that could revolutionize cancer therapy.

The Mechanism of Vonlerolizumab Action

Understanding OX40: The Secret of Tumor Immunity

OX40 (or called CD134, TNFRSF4) is a co-stimulatory receptor expressed on activated T cells. It belongs to the tumor necrosis factor receptor superfamily, along with TNFR1, TNFR2, and CD27. OX40 regulates T cell activation, proliferation, and survival, particularly during immune responses to infection and tumors. It is a receptor that does not exist naturally on unseasoned T cells but is activated upon activation of T cells. This signaling by OX40 provides a survival stimulus that inhibits the death of T cells and promotes the growth of effector T cells.

OX40 regulates immunity against T cells in two ways: it both promotes the growth and survival of effector T cells and suppresses the effects of regulatory T cells. Regulatory T cells, which suppress immune activity, can even suppress anti-tumor immune responses. Therefore, blocking Treg activity and increasing effector T cell responses provides a double action plan for cancer immunotherapy. So, OX40 represents an attractive target for cancer therapy.

How Vonlerolizumab Works?

Vonlerolizumab is an agonistic monoclonal antibody that binds specifically to OX40, which mimics the endogenous OX40 ligand (OX40L). Upon ingestion, this antibody selectively stimulates OX40 on effector T cells and causes a cascade of immune responses. Vonlerolizumab binding to OX40 helps these T cells survive, expand, and become active—all the factors necessary to find and kill tumor cells. Moreover, the antibody also inhibits Tregs to enhance the anti-tumor immune response.

Vonlerolizumab has a profound effect on T cell populations. Vonlerolizumab activates OX40, which drives the expansion of effector T cells capable of attacking TAAs. TAAs attached to cancer cells make them targets for the immune system, and the greater activation of effector T cells means a greater immune attack on the tumor. Moreover, when Treg activity is inhibited, these cells are not blocked from hijacking the immune system and killing the tumor cells more effectively.

OX40 on T cells allows the immune system to more efficiently fight off cancer cells. Several mechanisms of immune defense are frequently used by tumor cells to avoid immune detection, including Treg-mediated immune suppression. Vonlerolizumab's capacity to inhibit Treg suppression and stimulate effector T cell activation could represent a potentially useful approach to overcome tumor immunity to immune assault. This duality could augment the overall efficacy of cancer immunotherapy, especially in less well-responding tumors.

Figure 1. The Mechanism of TNFRSF Agonistic Antibody (Vonlerolizumab) Action.¹

The Clinical Applications of Vonlerolizumab

The promise of vonlerolizumab for cancer treatment is not only in how it works but in how well it can be used against all forms of cancer. Vonlerolizumab's immunostimulatory activity, as evaluated in preclinical models, is promising in facilitating T cell-mediated tumor rejection. Now, in ongoing clinical trials, it's being studied in conjunction with other immunotherapies like immune checkpoint inhibitors to augment its anti-cancer effect. For instance, vonlerolizumab could be used with checkpoint inhibitors such as pembrolizumab, since both treatments seek to defeat immune evasion. Although checkpoint inhibitors suppress PD-1/PD-L1 traffic, which tumors routinely exploit to escape immune detection, vonlerolizumab brings a complementary action of directly promoting T cell activation via OX40.

Personalized medicine is one of vonlerolizumab's greatest promises. Each tumor's immune profile is different: some tumors have high Treg infiltration and others are immune resistant because of low T cell activation. The selective inhibition of OX40 by vonlerolizumab enables immunotherapy to be tailored to a patient's specific tumor immunology. Knowing patients with a high Treg level or a low OX40 expression can help doctors tailor treatments to deliver better results.

Clinical Projects of Vonlerolizumab*

* The table was excerpted from the following website: https://clinicaltrials.gov/search?cond=MOXR-0916

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