pepinemab (VX15) / Vaccinex - LARVOL DELTA

Neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in resectable stage III melanoma (ESMO 2022) - P1 | "The combination of pepi/nivo/ipi provides robust pathologic response, durable response, and suitable toxicity. Analysis of biomarker endpoints is ongoing and will inform further development of this regimen."

Clinical • Combination therapy • Melanoma • Oncology • Solid Tumor

Neoadjuvant biomarker trial of pepinemab to enhance nivolumab or ipilimumab activity in resectable head and neck cancer. (ASCO 2025) - P1 | "Neoadjuvant treatment with pepi enhanced the density and maturity of TLS deep within the tumor which was most prominent in combination with nivo notably in HPV-negative disease. Pepi represents a novel strategy to boost tumor immunity and organization of functional TLS to overcome limitations of ICB in HPV- HNSCC."

Biomarker • Clinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD21 • FCER2 • SEMA4D

Adoptive T Cell Therapy Following HER2-Pulsed Dendritic Cell Vaccine & Pepinemab /Trastuzumab in Patients w/ Metastatic HER2+ Breast Cancer (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Dec 2025 ➔ Apr 2026

Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PGR

Drug Development. (PubMed, Alzheimers Dement) - P1/2, P2 | "Given the many physiological parallels between glial activation and inflammatory processes in HD and AD, results from these studies suggest that preventing astrocyte activation and reducing brain inflammation and associated vascular disruption with pepinemab treatment could be an attractive alternative or complement to anti-Aβ antibodies and support the broad application of glial regulators to treat cognitive dysfunction and neurodegenerative disease."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Huntington's Disease • Inflammation • Movement Disorders • Multiple Sclerosis • FAP • GFAP • LILRB4 • PLXNB1 • SEMA4D

Vaccinex…announced that it has entered into a $60 million revenue sharing agreement with Pepinemab Development Venture, LP (PDV) to continue advancing development of its pepinemab anti-SEMA4D antibody in an enlarged phase 2b clinical trial for treatment of AD (GlobeNewswire) - "The agreements provide that, in exchange for the commitment of funding, PDV will receive 50% of future economic proceeds received by Vaccinex from a development partner or licensee of pepinemab related to neurological indications and 25% related to other indications. This agreement follows on promising data previously reported from studies in animal disease models and in the early stage SIGNAL-AD phase 1/2a clinical trial..."

Financing • Licensing / partnership • Alzheimer's Disease

Biomarkers Associated with Response to Treatment of Early Stage AD with Pepinemab, Anti-SEMA4D Blocking Antibody (CTAD 2025) - No abstract available

Biomarker • Alzheimer's Disease • CNS Disorders • SEMA4D

Neoadjuvant pepinemab enhances immune checkpoint blockade in metastatic melanoma characterized by biomarkers of TME reprogramming including tertiary lymphoid structures (SITC 2025) - P1 | "Pepinemab, a novel semaphorin 4D (Sema4D) blocking antibody, reprograms myeloid-driven immune suppression and activates dendritic cells within the tumor microenvironment (TME), offering a complementary mechanism to enhance ICI efficacy.1 2Methods The phase II integrated biomarker clinical trial (NCT03769155) evaluated neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in patients with resectable metastatic melanoma. Mature (mTLS) defined as CD21+/- CD23+ CD20+ aggregates. Squares denote an event (recurrence or death)"

Biomarker • Checkpoint block • Checkpoint inhibition • Clinical • IO biomarker • Metastases • Melanoma • Oncology • Solid Tumor • CD20 • CD21 • CD4 • CD8 • FCER2 • SEMA4D

Neoadjuvant pepinemab enhances immune checkpoint blockade in metastatic melanoma characterized by biomarkers of TME reprogramming including tertiary lymphoid structures (SITC 2025) - P1 | "Pepinemab, a novel semaphorin 4D (Sema4D) blocking antibody, reprograms myeloid-driven immune suppression and activates dendritic cells within the tumor microenvironment (TME), offering a complementary mechanism to enhance ICI efficacy.1 2Methods The phase II integrated biomarker clinical trial (NCT03769155) evaluated neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in patients with resectable metastatic melanoma. Mature (mTLS) defined as CD21+/- CD23+ CD20+ aggregates. Squares denote an event (recurrence or death)"

Biomarker • Checkpoint block • Checkpoint inhibition • Clinical • IO biomarker • Metastases • Melanoma • Oncology • Solid Tumor • CD20 • CD21 • CD4 • CD8 • FCER2 • SEMA4D

VX15/2503 in Combination With Ipilimumab or Nivolumab in Patients With Head and Neck Cancer (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: Emory University | Trial completion date: Nov 2025 ➔ Nov 2027 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Biomarker • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Regulation of Vascular Calcification by M1-Type Macrophage-Derived Semaphorin 4D. (PubMed, Int J Mol Sci) - "Notably, neutralization of Sema4D in M1 conditioned medium using pepinemab, an anti-Sema4D antibody, effectively attenuated VSMC calcification induced by M1 macrophages. Conversely, supplementation of conditioned medium with recombinant Sema4D enhanced calcification and osteogenic signaling in VSMCs, further supporting the pro-calcifying role of Sema4D. Collectively, these findings highlight macrophage-derived Sema4D as a pivotal regulator of vascular calcification and a promising therapeutic target."

Journal • Atherosclerosis • Cardiovascular • SEMA4D

Vaccinex to Report Promising New Clinical Results of Neoadjuvant Treatment with Pepinemab to Enhance Immunotherapy in Patients with Head and Neck Cancer at ASCO Annual Meeting (GlobeNewswire) - P1 | N=50 | NCT03690986 | "Pepinemab has potential to be a major advance for HNSCC patients with cold and resistant disease, with capacity of a well-tolerated and effective treatment that can induce formation and harness the power of TLS to optimize the clinical benefit of immunotherapy. Our data demonstrate that the addition of pepinemab to neoadjuvant immune checkpoint treatments did not compound toxicities, yet it enhanced TLS maturity that correlated with improved pathologic response. Collectively, these results highlight the potential of pepinemab to turn immunologically cold tumors, such as HPV-negative head and neck cancer, into hot immune centers by inducing robust and mature TLS."

P1 data • Squamous Cell Carcinoma of Head and Neck

Trial of Immunotherapy With Avelumab and Pepinemab As Second Line For Patients With Metastatic Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=48 | Active, not recruiting | Sponsor: Vaccinex Inc. | Recruiting ➔ Active, not recruiting | Phase classification: P1b/2 ➔ P1/2

Enrollment closed • Phase classification • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

Regulating dendritic cells to promote mature tertiary lymphoid structures and enhance anti-tumor immunity (AACR 2025) - P1, P1/2 | "KEYNOTE-B84 study (NCT04815720) evaluated the safety and efficacy of pepinemab in combination with pembrolizumab as a first-line treatment for immunotherapy-naïve patients with R/M HNSCC. Neoadjuvant studies in patients with surgically resectable metastatic melanoma (NCT03769155) and HNSCC (NCT03690986) received pepinemab treatment combined with nivolumab and/or ipilimumab...When combined with ICI, pepinemab induced de novo formation of TLS that correlated with clinical benefit, even in poorly immunogenic tumors that do not respond well to ICI, including HPV-negative and PD-L1 low HNSCC. When combined with modalities to further expand DC, SEMA4D blocking antibodies inhibited tumor growth in preclinical models, including in ICI-resistant models."

IO biomarker • Head and Neck Cancer • Melanoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CD8 • CXCR5 • FLT3 • PD-L1 • SEMA4D

Neoadjuvant pepinemab enhances DC function associated with mature tertiary lymphoid structures and activity of immune checkpoint blockade in patients with metastatic melanoma (AACR 2025) - P1 | "A neoadjuvant window of opportunity study was designed to evaluate activity and efficacy of pepinemab, SEMA4D blocking antibody, combined with nivolumab (nivo) and/or ipilimumab (ipi) in patients with surgically resectable metastatic melanoma. All patients receiving triple combination therapy (8/8) were recurrence-free at 24 months with mature TLS in the resected tumors (6/6). Pepinemab represents a novel strategy to boost dendritic cell infiltration, activation, and organization of functional TLS to overcome limitations of ICB."

Checkpoint block • Checkpoint inhibition • Clinical • IO biomarker • Metastases • Melanoma • Oncology • Solid Tumor • CD163 • CD4 • CDK1 • CXCR5 • FLT3 • SEMA4D

Defining the mechanism of semaphorin4D tumorigenesis in prostate cancer models (AACR 2025) - "Loss of SEMA4D function could disrupt vascularization, creating hypoxia that induces tumor cell apoptosis. Two mouse models—subcutaneous Myc-CaP allografts in immunocompetent mice and Hi-Myc prostate cancer GEMM were treated with a SEMA4D blocking mAb (pepinemab) to inhibit SEMA4D signaling... Our findings suggest that SEMA4D inhibition effectively arrests tumor growth by disrupting angiogenesis and potentially regulating immune activity, alongside inducing hypoxia and apoptosis. Ongoing transcriptomic analyses will further explore molecular mechanisms, including pathways involved in angiogenesis and immune regulation."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • SEMA4D

Vaccinex to Report Promising New Clinical Data Revealing Pepinemab’s Unique Mechanism to Enhance Immunotherapy at Annual Meeting of American Association for Cancer Research (AACR) (GlobeNewswire) - "Vaccinex, Inc...today announced that it will present exciting new data characterizing the unique mechanism of pepinemab to enhance immune responses to checkpoint therapies, corresponding with improved survival benefit in patients with melanoma and head and neck cancer at the 2025 Annual Meeting of American Association for Cancer Research (AACR) in Chicago on April 29, 2025."

Clinical data • Head and Neck Cancer • Melanoma

SEMAPHORIN 4D BLOCKING ANTIBODY PEPINEMAB REVERSES ΑLPHA -SYNUCLEIN -INDUCED DAMAGE TO BLOOD BRAIN BARRIER IN A HUMAN BRAIN -ON-A-CHIP MODEL (ADPD 2025) - "SEMA4D is a key effector molecule with multi -faceted mechanisms of action. These results, together with prior clinical experience and favorable tolerability of pepinemab in clinical studies, support the broad application and development of pepinemab in neurodegenerati ve disease."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Huntington's Disease • Inflammation • Movement Disorders • SEMA4D

RESULTS OF SIGNAL-AD, A RANDOMIZED PHASE 1B/2 TRIAL EVALUATING SAFETY AND EFFICACY OF THE ANTI SEMA4D ANTIBODY PEPINEMAB IN AD. (ADPD 2025) - "Conclusions A statistically significant increase in metabolic activity and associated positive trends for plasma biomarkers and cognitive measures were observed for subjects with MCI. The Results suggest that pepinemab treatment is well tolerated and effective in people with MCI due to AD."

Clinical • P1/2 data • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • Solid Tumor • GFAP • SEMA4D

Pepinemab: a SEMA4D antagonist for treatment of Huntington's and other neurodegenerative diseases. (PubMed, Expert Opin Investig Drugs) - "Pepinemab's potential to reduce reactive gliosis and inflammation is a novel mechanism of action (MOA) that may be effective as a standalone therapy as well as one that may complement other strategies to reduce toxic disease associated processes. Pepinemab has demonstrated a favorable safety profile and treatment benefits in fluid biomarkers, imaging endpoints, and measures of cognitive function that encourage continued development in HD and other neurodegenerative diseases."

Journal • Review • Alzheimer's Disease • CNS Disorders • Huntington's Disease • Inflammation • Movement Disorders • Multiple Sclerosis • SEMA4D

VX15/2503 in Combination with Ipilimumab or Nivolumab in Patients with Head and Neck Cancer (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: Emory University | Trial completion date: Jul 2025 ➔ Nov 2025 | Trial primary completion date: Jul 2024 ➔ Jun 2025

Biomarker • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Adoptive T Cell Therapy Following HER2-Pulsed Dendritic Cell Vaccine & Pepinemab /Trastuzumab in Patients w/ Metastatic HER2+ Breast Cancer (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CD4 • HER-2 • PGR

Biomarkers. (PubMed, Alzheimers Dement) - P1/2 | "Given the many physiological parallels between glial activation and inflammatory processes in HD and AD, prior results from the SIGNAL-HD trial suggest that preventing astrocyte activation and reducing brain inflammation with pepinemab treatment could be an attractive alternative or complement to anti-Aβ antibodies."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders • Dementia • Huntington's Disease • Inflammation • Movement Disorders • Solid Tumor • FAP • GFAP • SEMA4D

KEYNOTE B84: Pepinemab in Combination With Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (clinicaltrials.gov) - P1/2 | N=49 | Completed | Sponsor: Vaccinex Inc. | Recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Jul 2024 | Trial primary completion date: Dec 2024 ➔ Jul 2024

Trial completion • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • IFNG • IL10 • IL2 • IL6 • PD-L1 • TGFB1 • TNFA

Pepinemab a semaphorin 4D blockade antibody in combination with immune checkpoint therapies induces mature lymphoid aggregates correlating with clinical outcomes (SITC 2024) - P1, P1/2 | "The KEYNOTE-B84 study (NCT04815720) evaluated the safety and efficacy of pepinemab in combination with pembrolizumab as a first-line treatment for immunotherapy-naïve patients with R/M HNSCC. Biomarker studies conducted in patients with surgically resectable metastatic melanoma (NCT03769155) and HNSCC (NCT03690986) received neoadjuvant treatment with pepinemab/nivolumab/ipilimumab combinations compared to nivolumab or ipilimumab alone...Increased density and maturity of lymphoid aggregates correlated with disease control and longer progression-free survival (PFS). Conclusions Pepinemab, a Semaphorin 4D (SEMA4D) blocking antibody, in combination with ICB converts 'Cold' tumors to 'Hot' by inducing organized lymphoid aggregates."

Clinical • Clinical data • Combination therapy • IO biomarker • Head and Neck Cancer • Melanoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CD4 • CD8 • CXCR5 • PD-L1 • PLXNB1 • SEMA4D

Vaccinex Reports Improved Immunity Correlating with Clinical Benefit of Pepinemab Combination Treatment at Society for Immunotherapy of Cancer’s Annual Meeting (GlobeNewswire) - "...Vaccinex will present data from the Phase 2 KEYNOTE-B84 study (NCT04815720) for treatment of recurrent and metastatic disease as well as an independent study evaluating neoadjuvant treatment of resectable HNSCC (NCT03690986) showing that pepinemab combination treatments appear to induce mature lymphoid aggregates correlating with clinical benefit within immunotherapy resistant tumor populations, including HPV-negative and PD-L1 low HNSCC."

Biomarker • Clinical data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck