Vaccinex, Inc. (Nasdaq: VCNX) is pioneering a differentiated approach to treating neurodegenerative disease through the inhibition of semaphorin 4D (SEMA4D), a key driver of neuroinflammation. The company’s lead drug candidate, pepinemab, blocks SEMA4D and has potential as a disease-modifying treatment for Huntington’s, Alzheimer’s and other neurodegenerative diseases.

Beyond neurology, Vaccinex has determined that, in combination with checkpoint inhibitors, pepinemab has potential to increase objective responses in oncology. The company additionally intends to leverage its proprietary drug discovery platform, ActivMAb®, to create opportunities for future pipeline expansion and strategic collaborations.



VX15/2503 (USAN Council approved name "pepinemab") is a humanized monoclonal IgG4 antibody that binds and blocks the signaling activity of SEMA4D. SEMA4D is an extracellular signaling molecule that regulates the migration and activation of immune and inflammatory cells at sites of injury and cancer. In chronic brain diseases, such as Huntington’s and Alzheimer’s disease, we have discovered that SEMA4D triggers neuroinflammation with an associated loss of normal brain functions that accelerates disease progression. Pepinemab’s mechanism of action is to block the SEMA4D signal so as to preserve normal functions and slow or prevent disease progression. In cancer, we discovered that tumors exploit expression of a high concentration of SEMA4D at their margins to block immune cell infiltration as one of several mechanisms to evade immune protection against cancer.

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.


Neurodegenerative diseases, such as Huntington's disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and progressive multiple sclerosis (MS), constitute some of the world’s most complex and difficult-to-treat disorders. Very few impactful treatment options exist for these conditions, which affect an estimated 6.5 million Americans. As the world’s population ages, there is an urgent need for the discovery and application of new therapeutic options.

Semaphorin 4D (SEMA4D) has been found to contribute to driving the neuroinflammation implicated in progression of these disorders, suggesting that blocking SEMA4D has promising potential as a new therapy for neurodegenerative diseases. Vaccinex is studying pepinemab’s potential for clinical benefit by blocking SEMA4D in Huntington’s and Alzheimer’s disease, and is exploring studies in other neurological indications.

Learn more about Pepinemab for Neurology


In addition to its broad potential for neurodegenerative diseases, pepinemab, in combination with a checkpoint inhibitor, has been found to have the potential to significantly enhance T-cell infiltration and reduce immunosuppressive cells in tumors, a potentially powerful combination to increase tumoricidal activity. Data from a Phase 1b/2 clinical trial in non-small cell lung cancer shows that the combination of pepinemab with BAVENCIO® (avelumab), appears to increase the frequency of objective responses and extend progression-free survival relative to single agent avelumab.

Learn more about Pepinemab for Immuno-oncology


Vaccinex has developed a fusion protein technology to enable the direct incorporation of multipass membrane proteins such as GPCRs and ion channels into the membrane of a mammalian virus. This method recovers the protein of interest naturally imbedded in the mammalian cell derived membrane, and because the whole virus is used, does not require any detergents or refolding in order to generate properly folded protein. This technology can be applied to multiple different cell types in order to maximize protein expression and to provide for any necessary chaperones. Antigen expressing virus can be readily purified and used for antibody selection using either in vitro display or immunization methods.

We use a similar fusion protein strategy with our antibody discovery platform that enables efficient mammalian cell based expression of a library of human antibodies in full length IgG format on the surface of both the mammalian virus and cell. The platform combines the advantages of virus panning and cell sorting into one seamless selection process. This technology enables the rapid selection of >1010 antibody combinations and thus selection of high affinity leads with varied frameworks that recognize multiple epitopes. The selected antibodies are ideally suited for development because they have already passed mammalian cell quality control during the selection process.

ActivMAb technology offers:

  • an innovative and efficient method for selecting antibodies against multi-pass membrane proteins, an important class of pharmacological targets.
  • rapid generation of high affinity, full-length, human monoclonal antibodies synthesized and naturally modified in mammalian cells,
  • evolution/optimization of protein expression by mutagenesis and selection for desired variants in a fully mammalian cell system.

Learn more about ActivMAb®