Biology subjects

Magnani, D. M.

Publications and source records attributed to Magnani, D. M..

6 recordsLinked to original sources

bioRxiv2025

Depletion and recovery of IgG following treatment with Rozanoliximab and Imlifidase in pigtail macaques

Antibodies are central players in adaptive immunity, providing protection against a wide array of pathogens through mechanisms such as neutralization, opsonization, recruitment of effector immune cells, complement activation and engagement. However, in other contexts, these same effector functions can contribute to immunopathology, particularly when antibodies are developed against self-antigens, resulting in autoimmunity. Understanding the role antibodies play in preventing or causing disease is often supported by studies in model systems wherein manipulation of IgG levels can be used as an experimental tool. Here, we report in simian immunodeficiency virus (SIV) infected pigtail macaques (Macaca nemestrina) the capacity of two orthogonal strategies to systemically deplete IgG - treatment with a neonatal Fc receptor blocking antibody (Rozanolixizumab) that restricts IgG rescue and recycling, and administration of the IgG protease Imlifidase (IdeS) that cleaves the Fc domain. Under the conditions evaluated, we observed more rapid and effective, although not necessarily more durable, IgG depletion mediated by IdeS, reducing levels by 74.1-95.1%, compared to a lesser reduction of 31.3-66.9% with anti-FcRn treatment. We observed a similar degree of depletion, comparable kinetics of rebound among SIV antigen-specific fractions as total IgG, but differential balance among IgG subclasses following treatment in some cases. In sum, this study in a nonhuman primate model describes the efficacy and downstream impacts of new tools to modify humoral immune states providing insight into the balance between protective and pathological effects of IgG antibodies.

immunology↗

bioRxiv2024

cMPL-Based Purification and Depletion of Human Hematopoietic Stem Cells: Implications for Pre-Transplant Conditioning

The transplantation of gene-modified autologous hematopoietic stem and progenitor cells (HSPCs) offers a promising therapeutic approach for hematological and immunological disorders. However, this strategy is often limited by the toxicities associated with traditional conditioning regimens. Antibody-based conditioning strategies targeting cKIT and CD45 antigens have shown potential in mitigating these toxicities, but their long-term safety and efficacy in clinical settings require further validation. In this study, we investigate the thrombopoietin (TPO) receptor, cMPL, as a novel target for conditioning protocols. We demonstrate that high surface expression of cMPL is a hallmark feature of long-term repopulating hematopoietic stem cells (LT-HSCs) within the adult human CD34+ HSPC subset. Targeting the cMPL receptor facilitates the separation of human LT-HSCs from mature progenitors, a delineation not achievable with cKIT. Leveraging this finding, we developed a cMPL-targeting immunotoxin, demonstrating its ability to selectively deplete host cMPLhigh LT-HSCs with a favorable safety profile and rapid clearance within 24 hours post-infusion in rhesus macaques. These findings present significant potential to advance our understanding of human hematopoiesis and enhance the therapeutic outcomes of ex vivo autologous HSPC gene therapies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/581887v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@10b265aorg.highwire.dtl.DTLVardef@102ec94org.highwire.dtl.DTLVardef@fa269dorg.highwire.dtl.DTLVardef@fd2583_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

cell biology↗

bioRxiv2023

Antibody-mediated depletion of select T cell subsets in blood and tissue of nonhuman primates

Understanding the immunological control of pathogens requires a detailed evaluation of the mechanistic contributions of individual cell types within the immune system. While knockout mouse models that lack certain cell types have been used to help define the role of those cells, the biological and physiological characteristics of mice do not necessarily recapitulate that of a human. To overcome some of these differences, studies often look towards nonhuman primates (NHPs) due to their close phylogenetic relationship to humans. To evaluate the immunological role of select cell types, the NHP model provides distinct advantages since NHP more closely mirror the disease manifestations and immunological characteristics of humans. However, many of the experimental manipulations routinely used in mice (e.g., gene knock-out) cannot be used with the NHP model. As an alternative, the in vivo infusion of monoclonal antibodies that target surface proteins on specific cells to either functionally inhibit or deplete cells can be a useful tool. Such depleting antibodies have been used in NHP studies to address immunological mechanisms of action. In these studies, the extent of depletion has generally been reported for blood, but not thoroughly assessed in tissues. Here, we evaluated four depleting regimens that primarily target T cells in NHP: anti-CD4, anti-CD8, anti-CD8{beta}, and immunotoxin-conjugated anti-CD3. We evaluated these treatments in healthy unvaccinated and IV BCG-vaccinated NHP to measure the extent that vaccine-elicited T cells - which may be activated, increased in number, or resident in specific tissues - are depleted compared to resting populations in unvaccinated NHPs. We report quantitative measurements of in vivo depletion at multiple tissue sites providing insight into the range of cell types depleted by a given mAb. While we found substantial depletion of target cell types in blood and tissue of many animals, residual cells remained, often residing within tissue. Notably, we find that animal-to-animal variation is substantial and consequently studies that use these reagents should be powered accordingly.

immunology↗

bioRxiv2023

A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions.

To eliminate vertical HIV transmission and achieve therapy-free viral suppression among children living with HIV, novel strategies beyond antiretroviral therapy (ART) are necessary. Our group previously identified a triple bNAb combination comprising of 3BNC117, PGDM1400 and PGT151 that mediates robust in vitro neutralization and non-neutralizing effector functions against a cross-clade panel of simian human immunodeficiency viruses (SHIVs). In this study, we evaluated the safety, pharmacokinetics, and antiviral potency of this bNAb combination in infant rhesus macaques (RMs). We demonstrate that subcutaneous infusion of the triple bNAb regimen was well tolerated in pediatric monkeys and resulted in durable systemic and mucosal distribution. Plasma obtained from passively-immunized RMs demonstrated potent HIV-neutralizing and Fc-mediated antiviral effector functions. Finally, using the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker, which was recently identified as a surrogate endpoint for evaluation of the preventative efficacy (PE) of bNAbs against mucosal viral acquisition in human clinical trials, we demonstrated that our regimen has a predicted PE[≥]90% against a large panel of plasma and breast milk-derived HIV strains and cross-clade SHIV variants. This data will guide the development of combination bNAbs for eliminating vertical HIV transmission and for achieving ART-free viral suppression among children living with HIV.

immunology↗

bioRxiv2020

Zika virus infection during pregnancy protects against secondary infection in the absence of CD8+ cells

While T cell immunity is an important component of the immune response to Zika virus (ZIKV) infection generally, the efficacy of these responses during pregnancy remains unknown. Here, we tested the capacity of CD8 lymphocytes to protect from secondary challenge in four macaques, two of which were depleted of CD8+ cells prior to rechallenge with a heterologous ZIKV isolate. The initial challenge during pregnancy produced transcriptional signatures suggesting complex patterns of immune modulation, but all animals efficiently controlled the rechallenge virus, implying that the primary infection conferred adequate protection. The secondary challenge promoted humoral responses and activation of innate and adaptive immune cells, suggesting a brief period of infection prior to clearance. These data confirm that ZIKV infection during pregnancy induces sufficient immunity to protect from a secondary challenge and suggest that this protection is not solely dependent on CD8 T cells but entails multiple arms of the immune system.

immunology↗

bioRxiv2017

Multiple introductions of Zika virus into the United States revealed through genomic epidemiology

Zika virus (ZIKV) is causing an unprecedented epidemic linked to severe congenital syndromes1,2. In July 2016, mosquito-borne ZIKV transmission was first reported in the continental United States and since then, hundreds of locally-acquired infections have been reported in Florida3. To gain insights into the timing, source, and likely route(s) of introduction of ZIKV into the continental United States, we tracked the virus from its first detection in Miami, Florida by direct sequencing of ZIKV genomes from infected patients and Aedes aegypti mosquitoes. We show that at least four distinct ZIKV introductions contributed to the outbreak in Florida and that local transmission likely started in the spring of 2016 - several months before its initial detection. By analyzing surveillance and genetic data, we discovered that ZIKV moved among transmission zones in Miami. Our analyses show that most introductions are phylogenetically linked to the Caribbean, a finding corroborated by the high incidence rates and traffic volumes from the region into the Miami area. By comparing mosquito abundance and travel flows, we describe the areas of southern Florida that are especially vulnerable to ZIKV introductions. Our study provides a deeper understanding of how ZIKV initiates and sustains transmission in new regions.

epidemiology↗