On September 26, 2023 SK Biopharmaceuticals, a global biotech focused on the research, development and commercialization of treatments for disorders of the central nervous system (CNS) and oncology, and its U.S. R&D subsidiary, Proteovant Therapeutics, reported that they will present data on the discovery and characterization of a selective IKZF2 molecular glue degrader with best-in-class potential, and on MOPED, a novel platform for the discovery of molecular glues, at the 20th Annual Discovery on Target Conference being held in Boston, September 25-28, 2023 (Press release, SK biopharmaceuticals, SEP 26, 2023, https://www.prnewswire.com/news-releases/sk-biopharmaceuticals-proteovant-therapeutics-presents-preclinical-data-on-ikzf2-protein-degrader-program-and-moped-molecular-glue-screening-platform-at-the-20th-annual-discovery-on-target-conference-301938441.html [SID1234635422]).

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These presentations are the first in a series in which the companies will unveil exciting results from its targeted protein degradation (TPD) studies and MOPEDTM Molecular Glue Screening Platform. TPD harnesses the body’s natural protein disposal system and offers the potential to develop new medicines targeting historically difficult-to-drug proteins that play an important role in causing serious diseases. SK Biopharmaceuticals and Proteovant Therapeutics are discovering and developing potential best-in-class and first-in-class degraders to engage previously undruggable targets.

"We are excited to share new data on our IKZF2 molecular glue degrader that demonstrates the potential to combine with immune checkpoint therapies for the treatment of cancer," said Donghoon Lee, President and CEO of SK Biopharmaceuticals and SK Life Science. "We are also pleased to present data showing how our MOPED platform can help find molecular glues with the potential to destroy malfunctioning proteins and kill cancer cells or inhibit their growth."

Discovery on Target Meeting Presentations:

Title: MOPED: A Novel Platform for the Discovery of Molecular Glues
Presenter: Corey Strickland, Ph.D.
Date/Time: Wednesday, September 27; 9:30 – 10:00 AM
Title: Discovery and Characterization of an IKZF2 Selective Molecular Glue Degrader with Best-in-Class Potential
Presenter: Courtney G. Havens, Ph.D.
Date/Time: Thursday, September 28; 2:50 – 3:20 PM

On September 26, 2023 Cue Biopharma, Inc. (Nasdaq: CUE), a clinical-stage biopharmaceutical company developing a novel class of injectable biologics to selectively engage and modulate disease-specific T cells directly within the patient’s body, reported that it has completed patient enrollment in its Phase 1 clinical trial (NCT03978689) evaluating CUE-101, the company’s lead interleukin 2 (IL-2)-based biologic from the CUE-100 series, in combination with KEYTRUDA (pembrolizumab) as first-line treatment for patients with human papilloma virus positive recurrent/metastatic head and neck squamous cell carcinoma (HPV+ R/M HNSCC) (Press release, Cue Biopharma, SEP 26, 2023, View Source [SID1234635421]).

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"Completing the enrollment of the recommended phase 2 dose patient expansion cohort is an important milestone as the data from this trial guides further development plans and associated discussions with the Food and Drug Administration (FDA)," said Daniel Passeri, chief executive officer of Cue Biopharma. "We believe the updated data will build upon the already promising clinical profile established to date, which has shown an enhancement of clinical efficacy with the CUE-101-pembrolizumab combination compared to pembrolizumab alone. With the strength of the data already observed with monotherapy in second line patients and beyond, combined with the promising combination data emerging in 1L with pembrolizumab, we plan to discuss potential registrational paths with the Food and Drug Administration (FDA) for CUE-101 both as a monotherapy and in combination with pembrolizumab, leveraging the Fast Track Designation previously granted to these programs."

Matteo Levisetti, M.D., chief medical officer of Cue Biopharma added, "We believe the data from our CUE-101 trial represents a potential therapeutic breakthrough for HPV+ R/M HNSCC patients, bolstering our confidence in the platform to address unmet needs of patients suffering from a myriad of cancers. The maturing clinical data for CUE-101 further supports the mechanism of action which enables selective expansion of targeted tumor-specific T cells and also provides clinical validation and de-risking of our Immuno-STAT platform. This clinical validation is also being supported by a Phase 1 trial with our second CUE-100 series biologic, CUE-102, for Wilms’ Tumor 1-expressing tumors. Data to date has demonstrated clinical evidence of anti-tumor activity across multiple indications in patients treated in the dose escalation portion of the study, and we look forward to presenting the data at SITC (Free SITC Whitepaper)."

About the CUE-100 Series
The CUE-100 series consists of Fc-fusion biologics that incorporate peptide-MHC (pMHC) molecules along with rationally engineered IL-2 molecules. This singular biologic is anticipated to selectively target, activate and expand a robust repertoire of tumor-specific T cells directly in the patient’s body. The binding affinity of IL-2 for its receptor has been deliberately attenuated to achieve preferential selective activation of tumor-specific effector T cells while reducing the potential for effects on regulatory T cells (Tregs) or broad systemic activation, potentially mitigating the dose-limiting toxicities associated with current IL-2-based therapies.

On September 26, 2023 Starpharma (ASX: SPL, OTCQX: SPHRY) reported the presentation of data that demonstrate the benefits of combining DEP irinotecan with other important classes of anti-cancer therapies, including immuno-oncology (IO) agents, in models of human colorectal cancer (Press release, Starpharma, SEP 26, 2023, View Source;mc_eid=bf52dd3418 [SID1234635420]). The data will be presented in Boston, US, at the AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), co-hosted by the American Association For Cancer Research (AACR) (Free AACR Whitepaper), the National Cancer Institute (NCI) and the European Organisation for Research and Treatment of Cancer (EORTC) from 11 to 15 October 2023. This poster presentation is one of three by Starpharma at the AACR (Free AACR Whitepaper)-NTI-EORTC conference showcasing multiple DEP programs, including DEP irinotecan and Starpharma’s radiotheranostic, DEP HER2-zirconium.

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This DEP irinotecan combination poster builds on Starpharma’s recently released positive clinical data on DEP irinotecan in advanced colorectal cancer (CRC) and advanced platinum-resistant ovarian cancer2.

The DEP irinotecan combination data to be presented show DEP irinotecan improves the anti-tumour activity of an IO agent3 in the same class as the highly successful Merck product, Keytruda (pembrolizumab), including in models of CRC that respond poorly to IO agents.

DEP irinotecan in combination with the IO agent enhanced anti-tumour responses compared to the IO agent alone in a CRC model that is only moderately responsive to the IO agent. The combination also resulted in complete tumour regression and prolonged survival compared to the IO agent alone in this CRC model. In another model of CRC that was not responsive to the IO agent alone, the anti-tumour effects of the combination of DEP irinotecan and the IO agent were enhanced when compared with either agent alone.

DEP irinotecan’s ability to elicit an anti-cancer response to an IO agent in an otherwise non-responsive CRC tumour is significant. These improved results in CRC models provide a rationale for a potentially important new application of DEP irinotecan in combination with IO agents, which are a leading and growing class of anticancer therapies.

Importantly, 85% to 95% of CRC patients do not respond to IO agents, such as Keytruda, and this cancer remains a significant unmet medical need. These CRC patients do not respond to IO agents because their cancer is classified as microsatellite stable (MSS). These MSS cancers are more difficult to treat, more likely to recur, and typically less responsive to IO therapies than cancers that are not MSS. This DEP irinotecan poster includes new clinical data from Starpharma’s Phase 1/2 trial of the product showing that all CRC patients who responded to DEP irinotecan were MSS and, therefore, in the category that is more difficult to treat.

IO agents have changed the landscape of cancer treatment, demonstrating impressive results in treating a number of cancers, including lung cancer and melanoma, and generating over USD $60.3 billion in sales in 2021, with sales predicted to grow 14 to 17% per year to 20264.

IO anti-cancer drugs are designed to disrupt normal immune processes, allowing the body’s immune cells to effectively target and destroy cancer cells. Currently marketed IO drugs include Keytruda (Merck), Opdivo (BMS), Yervoy (BMS), Tecentriq (Genentech), and Imfinzi (AstraZeneca). The global colorectal cancer drugs market was valued at ~US$14 billion in 2023 and is forecast to reach more than US$16 billion by 20275. Immunotherapies, such as Keytruda, had approximately 25% market share in 20186.

Despite their impressive efficacy, IO agents can cause serious immune-mediated adverse events that are challenging to manage. Treatment with DEP irinotecan resulted in no immune-mediated adverse events in CRC and ovarian patients, and therefore, there was no overlap of adverse events with those reported for IO agents – another benefit for this combination application.

In addition to the promising data for DEP irinotecan in combination with the IO agent, Starpharma’s poster also includes data on DEP irinotecan in combination with AstraZeneca’s Lynparza (olaparib). Olaparib is from a class of drugs called PARP inhibitors. DEP irinotecan also showed a synergistic effect in combination with olaparib in a model of CRC. The CRC model used was resistant to olaparib alone, but the combination of DEP irinotecan and olaparib achieved increased anti-tumour effects compared to DEP irinotecan alone, and also prolonged survival.

Lynparza had global sales of more than US$2.6 billion in 20227 and is approved for use in ovarian, breast, pancreatic and prostate cancers.

The data showing DEP irinotecan enhances anti-tumour responses of the IO agent and PARP inhibitor in models of cancer, together with the promising clinical efficacy and safety profile of DEP irinotecan in CRC and ovarian cancer, provide a strong rationale for clinical evaluation of DEP irinotecan in combination with IO agents and PARP inhibitors. These combination regimens are commercially important because they increase the potential market opportunities for DEP irinotecan and illustrate synergies with successful product categories. Given these findings, Starpharma is engaging in discussions with potential commercial partners, including companies that currently market IO agents.

The above-mentioned poster is one of three posters Starpharma is presenting at the AACR (Free AACR Whitepaper)-NCI-EORTC conference in October 2023.

Thursday, 12 October (Poster Session A): A147: A HER2 targeted polylysine dendrimer nanoparticle radiotheranostic demonstrates excellent tumor accumulation, rapid clearance from circulation, and promising performance in PET-CT imaging.
Friday, 13 October (Poster Session B): B039: A phase 1/2 study of dendrimer-enhanced (DEP) SN38 (SN38-SPL9111 / DEP irinotecan) in patients with advanced solid tumours.
Saturday, 14 October (Poster Session C): C167: An SN38 dendrimer nanoparticle, DEP irinotecan (SN38-SPL9111), demonstrates efficacy in mouse models of gastrointestinal cancer and augments anti-tumor effects of immune checkpoint blockade and PARP inhibition.
Abstracts, which include a summary of the data, will be published on the conference website ahead of the conference, and the full posters will be made available by Starpharma following publication.

About DEP irinotecan

DEP irinotecan is a novel, patented, nanoparticle formulation of SN38, the active metabolite of the widely used anti-cancer drug, irinotecan (marketed as Camptosar), delivered using Starpharma’s proprietary DEP technology. Camptosar and all generic forms of conventional irinotecan carry ‘black box’ warnings mandated by the US Food and Drug Administration (FDA) for both neutropenia and severe diarrhoea, which can be dose-limiting and life-threatening. DEP irinotecan has not resulted in severe diarrhoea in Phase 2 studies. DEP irinotecan has patent filings to 2039 and up to an additional five years.

The severe diarrhoea caused by conventional irinotecan results from the production of toxic metabolites during the liver metabolism of irinotecan to SN38. DEP irinotecan was designed to eliminate the need for liver metabolism, thereby avoiding the production of toxic metabolites.

About Starpharma’s DEP irinotecan Phase 2 clinical trial

Starpharma is evaluating DEP irinotecan as both a monotherapy and in combination with 5-fluorouracil (5-FU) and leucovorin (LV), which is a standard irinotecan combination regimen used in the treatment of CRC known as "FOLFIRI". The Phase 2 DEP irinotecan trial is being conducted at multiple sites, including Guy’s Hospital in London, Beatson Cancer Centre in Glasgow, Imperial College London, and the Kinghorn Cancer Centre in Sydney.

Clinical and commercial opportunity for DEP irinotecan

The global colorectal cancer drugs market was valued at ~US$14 billion in 2023 and is forecast to reach more than US$16 billion by 20278.

Camptosar and generic forms of conventional irinotecan are standard-of-care treatments for advanced CRC, with Pfizer’s Camptosar achieving peak sales of ~US$1.1 billion. CRC accounts for approximately 10% of all new cancer diagnoses and is the second leading cause of cancer, affecting more than 1 million people annually, and is the fourth leading cause of cancer-related death.

CRC incidence is increasing markedly among younger age groups, with rates of colon cancer more than doubling in adults aged 20 to 54 since the 1990s. Studies have shown that, compared with adults born around 1950, those born around 1990 have double the risk of colon cancer and quadruple the risk of rectal cancer.

On September 26, 2023 4SC AG (4SC, FSE Prime Standard: VSC) reported that it has received notification that US Food and Drug Administration (FDA) has granted 4SC’s application for Orphan Drug Designation for resminostat (Kinselby) for cutaneous T cell lymphoma (CTCL) (Press release, 4SC, SEP 26, 2023, https://www.pressetext.com/news/20230927006 [SID1234635419]).

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Jason Loveridge, Ph.D., CEO of 4SC, commented: "Receiving orphan drug designation for resminostat provides us with a number of important benefits, most crucially 7 years’ market exclusivity in the US, a key foundation of our efforts to commercialise Kinselby. We are currently preparing a marketing authorisation application for Kinselby in the EU, which remains on track for submission in Q1 2024."

On September 26, 2023 Vaccinex, Inc. (Nasdaq: VCNX), a clinical-stage biotechnology company will report on novel findings for its lead product, pepinemab, with implications for treatment of Alzheimer’s and other slowly progressive neurodegenerative diseases and for cancer immunotherapy at two upcoming Medical Conferences (Press release, Vaccinex, SEP 26, 2023, View Source [SID1234635418]).

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Results from our phase 2 SIGNAL trial suggest pepinemab is the first therapeutic agent that appears to have the potential to prevent decline in brain metabolic activity and to slow or halt cognitive decline in Huntington’s disease (HD) [1], a slowly progressive, orphan neurodegenerative disease with many pathological similarities to the much more prevalent Alzheimer’s disease (AD). Encouraged by these findings, a separate, randomized, phase 1/2a study in AD is ongoing in which the last patient is anticipated to complete the planned 12-months of treatment in early June 2024.
Pepinemab in combination with a checkpoint inhibitor is, to our knowledge, the first treatment that has shown the potential to induce formation of lymphoid structures in tumors that promote efficient immune responses and are known to be associated with improved outcomes in head and neck cancer. Clinical results indicate an approximate doubling of objective responses (ORR) and progression free survival (PFS) relative to historical results with checkpoint monotherapy in patients with hard-to-treat tumors that express low levels of PD-L1 (CPS<20) (described in detail below).
Alzheimer’s Disease

Vaccinex completed enrollment in the randomized, double-blind SIGNAL-AD phase 1/2a study (NCT04381468) for early AD in May 2023. The last patient is anticipated to complete the planned 12 months of treatment by early June 2024 at which time the database will be locked and results analyzed. Key endpoints include brain metabolic activity (FDG-PET, a biomarker of disease progression) along with measures of cognition specific to AD (CDR-SB, ADAS-Cog13) that have been recognized as clinically meaningful by the U.S. Food and Drug Administration (FDA). Investors will be aware of recent excitement surrounding full FDA approval of Eisai and Biogen’s drug Leqembi (lecanemab), the first anti-Aβ amyloid antibody for treatment of AD. A second such drug from Eli Lilly, donanemab, has reported equivalent data and may be FDA approved before year end. Clinical consensus is that Leqembi and donanemab provide a modest but real benefit to patients at a very early stage of disease. Common side effects associated with these drugs, however, include an inflammatory and hemorrhagic response in brain denoted as ARIA. Although ARIA often resolves itself, it has proven to be life-threatening in a small percentage of patients. As a result, all patients treated with these drugs must be followed carefully with significant effort and expense to avoid complications. It is important to appreciate that pepinemab has a very different mechanism of action than Leqembi or donanemab and, in clinical studies conducted to date, has not been found to be associated with inflammatory responses in the brain.

We believe that use of pepinemab to treat slowly progressive neurodegenerative diseases like AD has been substantially de-risked by results from our completed phase 2 study in HD. We have had the opportunity to meet with several major pharmaceutical companies. We believe from their responses that they have prioritized improving treatments for AD ("Our team was really intrigued by the data you presented and would like to continue our dialogue. However, we see your upcoming AD data as being essential to confirm the signal obtained in HD, and we would therefore gladly re-engage then."; "…we are enthused by the mechanism of Sema4D. We would be interested in re-engaging once your on-going Phase 2 [AD] is available."; "Let’s meet again when you are able to discuss the AD data with pepinemab.")

We believe that the prevalence of AD (6 million people diagnosed with AD in the US alone) and current concerns about the limitations of anti-Aβ amyloid antibodies would make pepinemab attractive as a potential alternative to anti-Aβ antibodies or possibly for use in combination with an anti-Aβ for greater efficacy. The potential impact of the AD program on Vaccinex valuation and financial resources, therefore, make this Vaccinex’s most important near term catalyst. Our highest priority in the coming months will be to complete the SIGNAL-AD trial, which we believe may make substantial resources available for our initiatives in cancer and other neurodegenerative diseases such as HD.

Cancer

The Phase 2 KEYNOTE-B84 study (NCT04815720) evaluated Vaccinex’s pepinemab antibody in combination with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) for immunotherapy of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Results of a preplanned interim analysis of the first 36 patients treated in this study indicated that the Objective Response (ORR) for the PD-L1 low population, CPS <20 (N=19), was 21.1% (2 CR and 2 PR) and median progression free survival (PFS) was 5.79 months, which are approximately twice that of historical ORR and PFS for checkpoint monotherapy in this population [2]. In contrast, in the CPS ≥20 (N=17) subgroup, the ORR and PFS for combination therapy was similar to historical checkpoint monotherapy. The improvement in response to treatment is important for the 55% of HNSCC patients whose tumors are characterized as CPS <20. These data are also consistent with a prior study in which we observed that the combination of pepinemab with PD-L1 inhibitor BAVENCIO (avelumab) appeared to approximately double ORR in patients with PD-L1-low non-small cell lung cancer (NCT03268057) [3].

In view of these clinical findings, we investigated the changes in the tumor immune environment that might correlate with response to pepinemab treatment by analyzing pre-treatment and on-treatment tumor biopsies collected during the KEYNOTE-B84 study. The results indicate that treatment with pepinemab in combination with KEYTRUDA appears to induce formation of highly organized lymphoid aggregates in the tumor of patients who demonstrate disease control (complete response plus partial response plus stable disease). Such aggregates are characterized by a high density of B cells, antigen-presenting dendritic cells and activated T cells (Figure 1A); further, treatment-induced increase in the number of aggregates correlates with Disease Control (Figure 1B) and with Progression Free Survival.

Representative images of 5-week on-treatment biopsies. Left: from a patient with stable disease, tumor biopsy contains highly organized immune aggregates consisting of high density antigen presenting cells (B cells, DC dendritic cells) as well as T lymphocytes. Right: from a patient with progressive disease, immune cells in the tumor biopsy are disorganized and include relatively high levels of inhibitory T regulatory (Treg) cells, but relatively few antigen presenting cells (B cells, DC).
Patients who experience clinical benefit (Disease Control) during treatment with pepinemab and KEYTRUDA have a higher frequency of mature immune aggregates with a high density of B cells in their on-treatment biopsy compared to their pre-treatment biopsies, p<0.0001. This difference is not observed in on- and pre-treatment biopsies from patients whose cancer progresses rapidly. One-way ANOVA, **** p<0.0001; ns = not significant, p≥0.05.
Immune Aggregates correlate with PFS. On-treatment patient biopsies with B cell aggregates positively correlate with longer progression-free survival. Log Rank survival analysis, p= 0.0056.
We and our collaborators at the Winship Cancer Center of Emory University have reported similar observations indicating that combination immunotherapy with pepinemab induces mature lymphoid structures in tumors of patients with metastatic melanoma treated in the neoadjuvant setting (NCT03690986) [4].

Based on these findings, we and our pharmaceutical collaborator, Merck Sharp & Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA, are in the preliminary testing and design stages of a potential extension of this study that may focus on treatment with pepinemab and KEYTRUDA in combination with chemotherapy. In previous studies of checkpoint monotherapy, addition of chemotherapy has been observed to approximately double the frequency of ORR. We believe that a similar effect is likely for addition of chemotherapy to treatment with pepinemab in combination with KEYTRUDA. We hope to subsequently determine whether, in the setting of more mature lymphoid structures in tumors, such treatment also prolongs overall survival.

Vaccinex has global commercial and development rights to pepinemab and is the sponsor of the KEYNOTE-B84 study which is being performed in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA. Additional information about the study is available at: clinicaltrials.gov.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

References:

1. Feigin AS, Evans EE, Fisher TL, et al. Pepinemab antibody blockade of SEMA4D in patients with early Huntington’s Disease: a randomized, placebo-controlled, Phase 2 trial. Nature Medicine, 2022 Aug 8;1-11. doi: 10.1038/s41591-022-01919-8.

2. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. The Lancet 2019; 394: 1915-1928. doi:10.1016/ S0140-6736(19)32591-7

3. Shafique MR, Fisher TL, Evans EE, Leonard JE, et al. A Phase Ib/II Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer. Clin Cancer Res. 2021 Jul 1;27(13):3630-3640. doi: 10.1158/1078-0432.CCR-20-4792.

4. Olson B, Mallow C, Reilly C, et al. Neoadjuvant SEMA4D blockade with nivolumab alters suppressive myeloid cells while elevating B cell and CD26hi T cell infiltration in the tumors of patients with resectable stage III melanoma. Journal for ImmunoTherapy of Cancer 2022;10: doi: 10.1136/jitc-2022-SITC2022.0613

About Pepinemab
Pepinemab is a humanized IgG4 monoclonal antibody designed to block SEMA4D, which can trigger collapse of the actin cytoskeleton and loss of homeostatic functions of astrocytes and glial cells in the brain and dendritic cells in immune tissue. Pepinemab has been administered to more than 400 patients and appears to be well-tolerated and to have a favorable safety profile.