Pepinemab Neurology

First in class,
anti-SEMA4D therapy
for neuroinflammatory and
neurodegenerative disease

Illustration of an antibody molecule in pink, purple and gray

Pepinemab is a novel monoclonal antibody that blocks the activity of Semaphorin 4D (SEMA4D). Preclinical testing has demonstrated beneficial effects of anti-SEMA4D treatment in multiple neurodegenerative disease models. Vaccinex is committed to the development of this important antibody that has the potential to help people with different neurodegenerative disorders that share common mechanisms of pathology.

Note: Pepinemab (VX15/2503) is an investigational drug currently in clinical studies. It has not been demonstrated to be safe and effective for any disease indication. There is no guarantee that pepinemab (VX15/2503) will be approved for the treatment of any disease by the U.S. Food and Drug Administration or by any other health authority worldwide.

Clinical Trials in Neurology

SEMA4D and PLXN expression in the brain

Astrocytes and microglia are key components of the brain that support neurons and shape neural networks by regulating formation and maintenance of synapses. Under conditions of physiological stress or injury, astrocytes and microglia transition from their normal function to an inflammatory state that can trigger or exacerbate neurodegeneration.

Video illustrating the role of SEMA4D on astrocytes and microglia under stress. Astrocytes support and interact with neurons and vasculature in the healthy brain. In the diseased brain, SEMA4D on neurons triggers reactive astrocytes with dysregulated function. Blockade of SEMA4D restores healthy astrocyte and neuronal function.

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In preclinical research, we demonstrated that SEMA4D is upregulated in neurons in response to stress or injury such as occurs during underlying progression of Alzheimer’s disease. Astrocytes and microglia express high affinity receptors for SEMA4D and are in close proximity to neurons. SEMA4D expression by neurons can, therefore, trigger inflammatory transformation of astrocytes.

This is the therapeutic rationale for use of pepinemab to treat neurodegenerative disorders. Pepinemab binds to SEMA4D and inhibits its activity, thereby preventing the increase in damaging inflammatory transformation and preserving essential normal astrocyte functions, including glucose transport and recycling of neurotransmitters.

SEMA4D has a dramatic effect on astrocyte morphology. In a healthy brain, astrocytes have long, thin extensions of their membranes that allow them to communicate with neurons and vasculature.

In an Alzheimer's Diseased brain, there is an increase of SEMA4D expression on neurons. When this SEMA4D binds to the receptors on the astrocytes, their long extensions collapse and communication between the cells is disrupted.

Healthy Brain