SEMA4D

引言骨分泌蛋白，称为骨因子，调节骨代谢和全身稳态。然而，关于真正的骨因子和它们的细胞来源是什么以及它们是如何被调节的基本问题仍然不清楚。2024年4月3日，南方医科大学白晓春、邹志鹏及中国科学院深圳先进技术研究院陈棣共同通讯在Cell Metabolism在线发表题为“An integrated multi-omics analysis reveals osteokines involved in global regulation”的研究论文，该研究分析了骨骼和骨骼外组织、成骨细胞(OB)条件培养基、骨髓上清(BMS)和血清，以寻找基础骨因子和那些对衰老和机械加载/卸载有反应的骨因子。通过整合RNA-seq、scRNA-seq和蛋白质组学方法的数据，该研究确定了375个候选骨因子及其对衰老和机械动力学的响应变化。此外，分析了它们在骨中的细胞来源和它们促进的器官间通讯(骨-脑、肝和主动脉)。值得注意的是，衰老的OBs分泌脂肪酸结合蛋白，使衰老向血管平滑肌细胞(VSMCs)传播。综上所述，该研究确定了以前未知的候选骨因子，并在它们之间建立了一个动态的调控网络，从而为进一步研究它们的系统作用提供了宝贵的资源。骨因子是指由骨产生和释放的一组细胞因子或肽，它们随后发挥自分泌、旁分泌和/或内分泌作用。骨是一种高度动态和代谢活跃的组织，在整个生命过程中经历不断的重塑以保持其强健的结构和功能，这一重塑过程涉及破骨细胞骨吸收和成骨细胞骨形成的协调作用。骨细胞(包括OBs细胞、破骨细胞、骨细胞、软骨细胞和骨髓基质细胞[BMSCs])之间广泛的分子通讯是精确调节骨形成和吸收的基本机制。OBs分泌多种骨因子，包括巨噬细胞集落刺激因子(M-CSF)，RANKL/OPG、SEMA3A和WNT5a调节破骨细胞的发生。此外，OBs分泌WNT4以自分泌方式促进骨形成，并以旁分泌方式抑制破骨细胞形成和吸收。骨细胞产生SOST抑制OB分化并促进破骨细胞分化。另一方面，破骨细胞分泌诸如CT-1、S1P、EphrinB2和SEMA4D等骨因子这些骨因子作用于OBs和骨细胞，影响成骨。此外，转化生长因子-β (TGF-β)调节破骨细胞OB串扰，将OB祖细胞募集到骨吸收部位，并促进骨形成。模式图（Credit: Cell Metabolism）近几十年来，骨生物学的重大进展揭示了骨的内分泌功能。骨源性FGF23调节肾脏中磷酸盐稳态的发现首次确立了骨作为内分泌器官的地位骨钙素促进胰岛素分泌和胰腺β细胞增殖，增加男性生育所需的睾酮生物合成，并修复神经变性导致的认知缺陷。另一个有趣的发现是OBs衍生的脂钙素-2 (LCN2)通过下丘脑的黑素皮质素4受体抑制食物摄入并调节葡萄糖水平。还报道了一系列调节骨髓微环境和造血的骨因子，如OBs衍生的CXCL9和骨细胞衍生的白细胞介素(IL)-34。这些发现表明骨因子在骨代谢和全身稳态中起重要作用。然而，现有的研究是有限的，缺乏整合。目前，对于骨因子的基本特征，如存在什么骨因子，从哪类骨细胞分泌骨因子，以及它们如何受环境因素的调节等，还缺乏全面的认识。此外，多组学方法提供了对生物学和疾病更全面的理解，使新的诊断和治疗靶点得以确定。该研究使用大量和单细胞转录组学和蛋白质组学进行了综合分析，以确定可能有助于骨代谢和全身稳态的骨因子。还鉴定了基础骨因子、衰老相关骨因子、机械反应性骨因子和OBs分泌骨因子(OBKs)，定位了它们在骨中的细胞来源，并分析了这些骨因子在器官间的通讯。孟德尔随机化(MR)分析显示，低骨密度(BMD)可能是动脉粥样硬化性心血管疾病(ASCVD)的潜在因果危险因素。衰老OBs分泌脂肪酸结合蛋白3 (FABP3)，使衰老向血管平滑肌细胞(VSMCs)扩散。总的来说，该研究建立了一个影响骨重塑和全局稳态的骨因子动态网络，为深入研究提供了宝贵的资源。原文链接https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cmet.2024.03.006责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

Expect Topline Data for Phase 1/2a Randomized SIGNAL-AD Study of Pepinemab for Alzheimer’s Disease in Q3 2024 Company raised $17.9 million of new financing during Q4 2023 and Q1 2024 ROCHESTER, N.Y., April 02, 2024 (GLOBE NEWSWIRE) --Vaccinex, Inc. (Nasdaq: VCNX), a clinical-stage biotechnology company pioneering a differentiated approach to treating neurodegenerative disease and cancer through the inhibition of SEMA4D, today announced financial results for the fourth quarter ended December 31, 2023 and provided a corporate update on key programs. Vaccinex achieved several important clinical milestones for pepinemab in both Alzheimer’s disease and Head and Neck Cancer. Alzheimer’s Disease (AD): In June 2024, anticipate completing planned 12-months treatment of patients with mild Alzheimer’s disease in the randomized, double-blind, Phase 1b/2a SIGNAL-AD trial of pepinemab vs placebo (NCT04381468). This study was funded in part by the Alzheimer’s Drug Discovery Foundation and by a grant from the Alzheimer’s Association. Topline data is expected in Q3 2024. Following last patient last visit we will evaluate the impact of treatment on brain metabolic activity, a key biomarker of clinical progression in AD, together with other biomarkers of disease progression and initial assessment of treatment effects on cognition employing several validated, clinically meaningful cognitive scales for AD. An improving AD-drug development environment, based on FDA’s recent full approval of LEQEMBI®, enables the pathway to reimbursement and supports partnering and further investment in Alzheimer’s Disease drug development. As previously reported, pepinemab has a differentiated mechanism of action, blocking SEMA4D, which is upregulated in neurons during stress of Alzheimer’s and Huntington’s disease and triggers the transformation of astrocytes and microglia from normal homeostatic functions to neuroinflammatory activity. Blockade of SEMA4D is believed to reduce neuroinflammation and to protect and restore healthy astrocyte and neuronal functions (Nature Medicine 2022, ). 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 anti-Aβ for greater efficacy. Head and Neck Cancer: As previously reported, analysis of interim data from the first 36 patients in the single-arm, Phase 2 KEYNOTE-B84 study (NCT04815720) evaluating pepinemab in combination with KEYTRUDA™ in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) suggests that the combination treatment resulted in an approximately 2X increase in objective responses (ORR) and progression free survival (PFS) in the subset of patients with hard-to-treat PD-L1-low tumors compared to historical response rates for checkpoint monotherapy in this population. Biomarker data indicate that treatment induced the formation of highly organized lymphoid aggregates in tumor that correlate with disease control and have previously been shown to be predictive of positive response to checkpoint inhibitors. Further research has suggested strategies to exploit this unique feature of pepinemab treatment in combination with KEYTRUDA so as to further enhance and expand treatment benefit. This will be the focus of continuing development. Financial Results for the Year Ended December 31, 2023: Cash and Cash Equivalents and Marketable Securities. Cash and cash equivalents and marketable securities on December 31, 2023 were $1.5 million, as compared to $6.4 million as of December 31, 2022. In October 2023, the Company raised gross proceeds of $9.6 million from the sale of common stock and warrants to purchase common stock to certain investors including entities controlled by Albert D. Friedberg, the chairman of the Company’s board of directors and Maurice Zauderer, President and CEO of Vaccinex. Subsequently, on February 8, 2024, the Company completed a private placement of common stock and warrants to purchase common stock for gross proceeds of $3.7 million and on March 28, 2024 raised $1.5 million in a public offering and an additional $1.24 million on similar terms in a parallel private placement of common stock and warrants to purchase common stock. The Company was very pleased to also receive a $1.75 million investment from the Alzheimer’s Drug Discovery Foundation (ADDF) on March 29, 2024 in a private placement of preferred stock together with a common warrant to purchase common stock. ADDF has been a leading and visionary supporter of research in AD for 25 years and this was the second such award received by Vaccinex from this distinguished foundation. Details of all these transactions are available in 8-K and other periodic reports filed with the Securities and Exchange Commission (S.E.C.). Research and Development Expenses. Research and development expenses for the year ended December 31, 2023, were $16.6 million as compared to $14.0 million for the comparable period in 2022. General and Administrative Expenses. General and administrative expenses for the year ended December 31, 2023 were $6.9 million as compared to $6.2 million for the comparable period in 2022. Comprehensive loss/Net loss per share. The Comprehensive Loss and Net loss per share for the year ended December 31, 2023, was $20.3 million and $(43.68) compared to $19.8 million and $(98.05) for the comparable period in 2022. Full financial tables are included below. The Company effected a 1-for-15 reverse stock split in Q3 2023 and 1-for-14 reverse stock split in Q1 2024. All share and share amounts have been retro-actively restated to give effect to the reverse stock splits. For further details on Vaccinex’s financials and the reverse stock splits, refer to its Form 10-K filed April 2, 2024, with the SEC. 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. Over 600 patients have been treated or enrolled in clinical trials of pepinemab in different indications and pepinemab appears to be well-tolerated and to have a favorable safety profile. About Vaccinex Inc. Vaccinex, Inc. is pioneering a differentiated approach to treating slowly progressive neurodegenerative diseases and cancer through the inhibition of semaphorin 4D (SEMA4D). The Company’s lead drug candidate, pepinemab, blocks SEMA4D, a potent biological effector that it believes triggers damaging inflammation in chronic diseases of the brain and prevents immune infiltration into tumors. In neurodegenerative diseases, pepinemab is being studied as a monotherapy in the Phase 1/2a SIGNAL-AD study in Alzheimer’s Disease, with ongoing exploration of potential Phase 3 development in Huntington’s disease. In oncology, pepinemab is being evaluated in combination with KEYTRUDA® in the Phase 1b/2 KEYNOTE-B84 study in recurrent or metastatic head and neck cancer (HNSCC) and in combination with BAVENCIO® in a Phase 1b/2 study in patients with metastatic pancreatic adenocarcinoma (PDAC). The oncology clinical program also includes several investigator-sponsored studies in solid tumors including breast cancer and melanoma. 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 Corp, a subsidiary of Merck and Co, Inc. Kenilworth, NJ, USA. Additional information about the study is available at: clinicaltrials.gov. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. BAVENCIO®/avelumab is provided by Merck KGaA, Darmstadt, Germany, previously as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany and Pfizer. Forward Looking Statements To the extent that statements contained in this presentation are not descriptions of historical facts regarding Vaccinex, Inc. (“Vaccinex,” “we,” “us,” or “our”), they are forward-looking statements reflecting management’s current beliefs and expectations. Such statements include, but are not limited to, statements about expectations and objectives with respect to the results and timing of the SIGNAL-AD clinical trial; our plans, expectations and objectives with respect to the results and timing of the KEYNOTE-B84 clinical trial; the use and potential benefits of pepinemab in R/M HNSCC, lung cancer, metastatic pancreatic adenocarcinoma (PDAC) and other indications; the potential for benefits as compared to single agent KEYTRUDA® or BAVENCIO®; expectations with respect to the collaboration of Merck; the potential to initiate a Phase 3 trial in Huntington’s Disease; and other statements identified by words such as “believe,” “being,” “will,” “appears,” “expect,” “ongoing,” “potential,” “suggest”, and similar expressions or their negatives (as well as other words and expressions referencing future events, conditions, or circumstances). Forward-looking statements involve substantial risks and uncertainties that could cause the outcome of our research and pre-clinical development programs, clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, uncertainties inherent in the execution, cost and completion of preclinical studies and clinical trials, that interim and preliminary data may not be predictive of final results and does not ensure success in later clinical trials, uncertainties related to regulatory approval, risks related to our dependence on our lead product candidate pepinemab, the possible delisting of our common stock from NASDAQ if we are unable to regain compliance with the NASDAQ listing standards, and other matters that could affect our development plans or the commercial potential of our product candidates. Except as required by law, we assume no obligation to update these forward-looking statements. For a further discussion of these and other factors that could cause future results to differ materially from any forward-looking statement, see the section titled “Risk Factors” in our periodic reports filed with the Securities and Exchange Commission and the other risks and uncertainties described in the Company’s annual year-end Form 10-K and subsequent filings with the SEC. Investor Contact Elizabeth Evans, PhD Chief Operating Officer, Vaccinex, Inc. (585) 271-2700 eevans@vaccinex.com VACCINEX, INC. Balance Sheets (in thousands, except share and per share data) As of December 31, 2023 As of December 31, 2022 ASSETS Current assets: Cash and cash equivalents $ 1,535 $ 6,391 Accounts receivable 961 175 Prepaid expenses and other current assets 853 912 Total current assets 3,349 7,478 Property and equipment, net 136 189 Operating lease right-of-use asset 146 310 TOTAL ASSETS $ 3,631 $ 7,977 LIABILITIES AND STOCKHOLDERS’ EQUITY Current liabilities: Accounts payable $ 2,039 $ 1,518 Accrued expenses 1,242 781 Deferred revenue 63 - Current portion of long-term debt 75 74 Operating lease liability 146 164 Warrant liability 2,351 - Total current liabilities 5,916 2,537 Long-term debt 26 101 Operating lease liability, net of current portion - 146 TOTAL LIABILITIES 5,942 2,784 Commitments and contingencies (Note 6) Stockholders’ equity (deficit): Common stock, par value of $0.0001 per share; 100,000,000 shares authorized as of December 31, 2023, and December 31, 2022; 892,622 and 237,532 shares issued as of December 31, 2023 and December 31, 2022, respectively; 892,617 and 237,527 shares outstanding as of December 31, 2023 and December 31, 2022, respectively - - Additional paid-in capital 337,627 324,880 Treasury stock, at cost; 5 shares of common stock as of December 31, 2023 and December 31, 2022, respectively (11 ) (11 ) Accumulated deficit (339,927 ) (319,676 ) TOTAL STOCKHOLDERS’ EQUITY/(DEFICIT) (2,311 ) 5,193 TOTAL LIABILITIES AND STOCKHOLDERS’ EQUITY $ 3,631 $ 7,977 VACCINEX, INC. Statements of Operations and Comprehensive Loss (in thousands, except share and per share data) Year Ended December 31, 2023 2022 Revenue $ 570 $ 275 Costs and expenses: Research and development 16,574 13,979 General and administrative 6,881 6,202 Total costs and expenses 23,455 20,181 Loss from operations (22,885 ) (19,906 ) Interest expense (1 ) (2 ) Financing costs - warrant liabilities (383 ) - Change in fair value of warrant liabilities 2,106 - Other income (expense), net 912 93 Loss before provision for income taxes (20,251 ) (19,815 ) Provision for income taxes - - Net loss attributable to Vaccinex, Inc. common stockholders $ (20,251 ) $ (19,815 ) Comprehensive loss $ (20,251 ) $ (19,815 ) Net loss per share attributable to Vaccinex, Inc. common stockholders, basic and diluted $ (43.68 ) $ (98.05 ) Weighted-average shares used in computing net loss per share attributable to Vaccinex, Inc. common stockholders, basic and diluted 463,653 202,082

ROCHESTER, N.Y., March 27, 2024 (GLOBE NEWSWIRE) -- Vaccinex, Inc. (Nasdaq: VCNX) (“Vaccinex” or the “Company”), a clinical-stage biotechnology company pioneering a differentiated approach to treating Alzheimer’s disease and cancer through the inhibition of SEMA4D, today announced that it has entered into definitive agreements with certain institutional investors for the purchase and sale of 193,000 shares of its common stock in a registered direct offering together with warrants to purchase up to an aggregate of 193,000 shares of common stock in a concurrent private placement priced at-the-market under Nasdaq rules at a combined purchase price of $7.77 per share and accompanying warrant. The warrants will have an exercise price of $7.64 per share, will be immediately exercisable upon issuance and will expire 5 years from the initial exercise date. The registered direct offering and concurrent private placement are referred to herein as the “Transactions.” The closing of the Transactions is expected to occur on or about March 28, 2024, subject to the satisfaction of customary closing conditions. The gross proceeds from the Transactions are expected to be approximately $1.5 million, before deducting financial advisory fees and other estimated expenses related to the Transactions. The Company intends to use the net proceeds from the Transactions for working capital and general corporate purposes. The registered direct offering of the shares of common stock is being made pursuant to an effective shelf registration statement on Form S-3 (File No 333-271074) previously filed with the U.S. Securities and Exchange Commission (the “SEC”). A prospectus supplement describing the terms of the registered direct offering will be filed with the SEC and will be available on the SEC’s website located at http://www.sec.gov. Electronic copies of the prospectus supplement may be obtained. The Company has also agreed to sell $1.1 million and up to $1.25 million in a separate private placement of common stock together with warrants to purchase shares of the Company’s common stock at the same combined purchase price as the Transactions. The closing of this transaction is also expected to occur on or about March 28, 2024. The private placement of the warrants and the separate private placement of common stock together with warrants are being made in reliance on an exemption from registration under Section 4(a)(2) of the Securities Act and/or Regulation D thereunder. This press release shall not constitute an offer to sell or the solicitation of an offer to buy nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. About Vaccinex Inc. Vaccinex, Inc. is pioneering a differentiated approach to treating slowly progressive neurodegenerative diseases and cancer through the inhibition of semaphorin 4D (SEMA4D). The Company’s lead drug candidate, pepinemab, is designed to block SEMA4D, a potent biological effector that is believed to trigger damaging inflammation in chronic diseases of the brain and to inhibit immune infiltration and activation in tumors. Pepinemab is being studied as a monotherapy in the Phase 1/2a SIGNAL-AD study in Alzheimer’s Disease that is expected to readout in Q3 2024, with ongoing exploration of potential Phase 3 development in Huntington’s disease. In oncology, pepinemab is being evaluated in combination with KEYTRUDA® in the Phase 1b/2 KEYNOTE-B84 study in recurrent or metastatic head and neck cancer (HNSCC) and in combination with BAVENCIO® in a Phase 1b/2 study in patients with metastatic pancreatic adenocarcinoma (PDAC). The oncology clinical program also includes several investigator-sponsored studies in solid tumors including breast cancer and melanoma. Forward Looking Statements This press release contains certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and Private Securities Litigation Reform Act, as amended, including those relating to the timing and completion of the proposed Transactions, the anticipated use of proceeds from the Transactions and other statements that are predictive in nature. These statements may be identified by the use of forward-looking expressions, including, but not limited to, “expect,” “anticipate,” “intend,” “plan,” “believe,” “estimate,” “potential,” “predict,” “project,” “should,” “would” and similar expressions and the negatives of those terms. These statements relate to future events and involve known and unknown risks, uncertainties and other factors which may cause actual results, performance or achievements to be materially different from any results, performance or achievements expressed or implied by the forward-looking statements. Such factors include the risk factors set forth in the Company’s filings with the SEC, including, without limitation, its Annual Report on Form 10-K, its periodic reports on Form 10-Q, and its Current Reports on Form 8-K, as well as the risks identified in the shelf registration statement and the prospectus supplement relating to the Transactions. Prospective investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this press release. Vaccinex undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Investor Contact Elizabeth Evans, PhDChief Operating Officer, Vaccinex, Inc.(585) 271-2700eevans@vaccinex.com