Author: Di, Mei ; Mostafavi, Mina ; Uyeda, Craig ; Lam, Sheung Kwan ; Primack, Ronya ; Wang, Zhe ; Poon-Andersen, Carrie ; Li, Peng ; Case, Ryan B. ; Cook, Kevin D. ; Soto, Marcus ; LaGory, Edward L. ; Dang, Khue ; Ouyang, Brian ; Devanaboyina, Siva Charan ; Ponce, Manuel ; Kaner, Joelle ; Thomas, Veena A.

Targeting antigens with antibodies exhibiting pH/Ca²⁺-dependent binding against an antigen is an attractive strategy to mitigate target-mediated disposition and antigen buffering. Studies have reported improved serum exposure of antibodies exhibiting pH/Ca²⁺-binding against membrane-bound receptors. Asialoglycoprotein receptor 1 (ASGR1) is a membrane-bound receptor primarily localized in hepatocytes. With a high expression level of approximately one million receptors per cell, high turnover, and rapid recycling, targeting this receptor with a conventional antibody is a challenge. In this study, we identified an antibody exhibiting pH/Ca²⁺-dependent binding to ASGR1 and generated antibody variants with increased binding to neonatal crystallizable fragment receptor (FcRn). Serum exposures of the generated anti-ASGR1 antibodies were analyzed in transgenic mice expressing human FcRn. Contrary to published reports of increased serum exposure of pH/Ca²⁺-dependent antibodies, the pH/Ca²⁺-dependent anti-ASGR1 antibody had rapid serum clearance in comparison to a conventional anti-ASGR1 antibody. We conducted sub-cellular trafficking studies of the anti-ASGR1 antibodies along with receptor quantification analysis for mechanistic understanding of the rapid serum clearance of pH/Ca²⁺-dependent anti-ASGR1 antibody. The findings from our study provide valuable insights in identifying the antigens, especially membrane bound, that may benefit from targeting with pH/Ca²⁺-dependent antibodies to obtain increased serum exposure.

01 Jun 2023·NatureQ1 · CROSS-FIELD

Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury.

Q1 · CROSS-FIELD

Article

Author: Lin, Zhonghua ; Alegre, Kamela ; Seshasayee, Dhaya ; Mossemann, Jan ; Deshpande, Ishan ; Kelly, Ryan L ; Lee, Wyne P ; Zhang, Juan ; Johnson, Matthew C ; Ali, Danish ; Wu, Shuang ; Stowe, Irma B ; Newton, Kim ; Dixit, Vishva M ; Lee, Bettina L ; Joshi, Prajakta ; Zhao, Sarah ; Kornfeld, Opher S ; Goldenberg, Neil M ; Lin, WeiYu ; Liu, John ; Kayagaki, Nobuhiko ; Schneider, Kellen ; Suto, Eric ; Steinberg, Benjamin E ; Webster, Joshua D ; Chalouni, Cecile ; Sayed, Blayne A ; Bhangale, Tushar

Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ1¹. PMR releases pro-inflammatory cytoplasmic molecules, collectively called damage-associated molecular patterns (DAMPs), that activate immune cells. Therefore, inhibiting NINJ1 and PMR may limit the inflammation that is associated with excessive cell death. Here we describe an anti-NINJ1 monoclonal antibody that specifically targets mouse NINJ1 and blocks oligomerization of NINJ1, preventing PMR. Electron microscopy studies showed that this antibody prevents NINJ1 from forming oligomeric filaments. In mice, inhibition of NINJ1 or Ninj1 deficiency ameliorated hepatocellular PMR induced with TNF plus D-galactosamine, concanavalin A, Jo2 anti-Fas agonist antibody or ischaemia-reperfusion injury. Accordingly, serum levels of lactate dehydrogenase, the liver enzymes alanine aminotransaminase and aspartate aminotransferase, and the DAMPs interleukin 18 and HMGB1 were reduced. Moreover, in the liver ischaemia-reperfusion injury model, there was an attendant reduction in neutrophil infiltration. These data indicate that NINJ1 mediates PMR and inflammation in diseases driven by aberrant hepatocellular death.

01 Jun 2013·The Journal of Sexual MedicineQ2 · MEDICINE

Nerve Injury-Induced Protein 1 (Ninjurin-1) is a Novel Therapeutic Target for Cavernous Nerve Injury-Induced Erectile Dysfunction in Mice

Q2 · MEDICINE

Article

Author: Park, JinMi ; Kim, KyuWon ; Ryu, JiKan ; Kwon, KiDong ; Batbold, Dulguun ; Choi, Min Ji ; Kim, Woo Jean ; Jin, HaiRong ; Suh, JunKyu ; Kwon, MiHye ; Song, KangMoon ; Das, Nando Dulal ; Yin, Guo Nan

ABSTRACTIntroductionRadical prostatectomy for prostate cancer can not only induce cavernous nerve injury (CNI) but also result in structural changes in the cavernous tissues. Nerve injuryinduced protein 1, Ninjurin1 (Ninj1), is known to be involved in neuroinflammatory processes and to be related to vascular regression during the embryonic period.AimThe study aims to determine whether and how Ninj1 neutralizing antibody (Ninj1Ab) restores erectile function in mice with CNI.MethodsTwelveweekold C57BL/6J mice were used and distributed into four groups: sham operation group and CNI groups receiving a single intracavernous injection of immunoglobulin G (IgG) control antibody, lowdose Ninj1Ab (1.0 μg/20 μL), or highdose Ninj1Ab (2.5 μg/20 μL).Main Outcome MeasuresOne week after bilateral cavernous nerve crush, erectile function was measured by electrical stimulation of the cavernous nerve. The penis was harvested for histologic examinations and Western blot analysis.ResultsThe cavernous expression of Ninj1 protein was upregulated up to 7 days after CNI and returned to baseline levels thereafter. Local delivery of Ninj1Ab significantly increased penile neuronal nitric oxide synthase and neurofilament contents, induced cavernous endothelial proliferation and phosphorylation of Akt and endothelial nitric oxide synthase, and decreased endothelial cell apoptosis in the CNI mice by upregulating angiopoietin1 and downregulating angiopoietin2. Highdose Ninj1Ab induced profound restoration of erectile function in the CNI mice (91% of sham control values), whereas lowdose Ninj1Ab elicited partial improvement.ConclusionThe dual neurotrophic and angiogenic effects of Ninj1 blockade may provide a good opportunity for treating erectile dysfunction resulting from radical prostatectomy.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Preclinical	US	Genentech, Inc.	16 May 2023

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