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Single-domain antibody-based protein degrader for synucleinopathies

Jiang, Yixiang; Lin, Yan; Tetlow, Amber M; Pan, Ruimin; Ji, Changyi; Kong, Xiang-Peng; Congdon, Erin E; Sigurdsson, Einar M
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.
PMCID:11140919
PMID: 38816762
ISSN: 1750-1326
CID: 5663902

Human CD4-binding site antibody elicited by polyvalent DNA prime-protein boost vaccine neutralizes cross-clade tier-2-HIV strains

Wang, Shixia; Chan, Kun-Wei; Wei, Danlan; Ma, Xiuwen; Liu, Shuying; Hu, Guangnan; Park, Saeyoung; Pan, Ruimin; Gu, Ying; Nazzari, Alexandra F; Olia, Adam S; Xu, Kai; Lin, Bob C; Louder, Mark K; McKee, Krisha; Doria-Rose, Nicole A; Montefiori, David; Seaman, Michael S; Zhou, Tongqing; Kwong, Peter D; Arthos, James; Kong, Xiang-Peng; Lu, Shan
The vaccine elicitation of HIV tier-2-neutralization antibodies has been a challenge. Here, we report the isolation and characterization of a CD4-binding site (CD4bs) specific monoclonal antibody, HmAb64, from a human volunteer immunized with a polyvalent DNA prime-protein boost HIV vaccine. HmAb64 is derived from heavy chain variable germline gene IGHV1-18 and light chain germline gene IGKV1-39. It has a third heavy chain complementarity-determining region (CDR H3) of 15 amino acids. On a cross-clade panel of 208 HIV-1 pseudo-virus strains, HmAb64 neutralized 20 (10%), including tier-2 strains from clades B, BC, C, and G. The cryo-EM structure of the antigen-binding fragment of HmAb64 in complex with a CNE40 SOSIP trimer revealed details of its recognition; HmAb64 uses both heavy and light CDR3s to recognize the CD4-binding loop, a critical component of the CD4bs. This study demonstrates that a gp120-based vaccine can elicit antibodies capable of tier 2-HIV neutralization.
PMCID:11109196
PMID: 38773089
ISSN: 2041-1723
CID: 5654492

Single-Domain Antibody-Based Protein Degrader for Synucleinopathies

Jiang, Yixiang; Lin, Yan; Tetlow, Amber M; Pan, Ruimin; Ji, Changyi; Kong, Xiang-Peng; Congdon, Erin E; Sigurdsson, Einar M
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.
PMCID:10979981
PMID: 38558982
CID: 5664352

Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function

Silberstein, John L; Du, Jasper; Chan, Kun-Wei; Frank, Jessica A; Mathews, Irimpan I; Kim, Yong Bin; You, Jia; Lu, Qiao; Liu, Jia; Philips, Elliot A; Liu, Phillip; Rao, Eric; Fernandez, Daniel; Rodriguez, Grayson E; Kong, Xiang-Peng; Wang, Jun; Cochran, Jennifer R
Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.
PMCID:10962948
PMID: 38483996
ISSN: 1091-6490
CID: 5639842

Transmembrane domain-driven PD-1 dimers mediate T cell inhibition

Philips, Elliot A; Liu, Jia; Kvalvaag, Audun; Mørch, Alexander M; Tocheva, Anna S; Ng, Charles; Liang, Hong; Ahearn, Ian M; Pan, Ruimin; Luo, Christina C; Leithner, Alexander; Qin, Zhihua; Zhou, Yong; Garcia-España, Antonio; Mor, Adam; Littman, Dan R; Dustin, Michael L; Wang, Jun; Kong, Xiang-Peng
Programmed cell death-1 (PD-1) is a potent immune checkpoint receptor on T lymphocytes. Upon engagement by its ligands, PD-L1 or PD-L2, PD-1 inhibits T cell activation and can promote immune tolerance. Antagonism of PD-1 signaling has proven effective in cancer immunotherapy, and conversely, agonists of the receptor may have a role in treating autoimmune disease. Some immune receptors function as dimers, but PD-1 has been considered monomeric. Here, we show that PD-1 and its ligands form dimers as a consequence of transmembrane domain interactions and that propensity for dimerization correlates with the ability of PD-1 to inhibit immune responses, antitumor immunity, cytotoxic T cell function, and autoimmune tissue destruction. These observations contribute to our understanding of the PD-1 axis and how it can potentially be manipulated for improved treatment of cancer and autoimmune diseases.
PMCID:11166110
PMID: 38457513
ISSN: 2470-9468
CID: 5669812

Short Carbon Nanotube-Based Delivery of mRNA for HIV-1 Vaccines

Xu, Yang; Ferguson, Tammy; Masuda, Kazuya; Siddiqui, Mohammad Adnan; Smith, Kelsi Poole; Vest, Olivia; Brooks, Brad; Zhou, Ziyou; Obliosca, Judy; Kong, Xiang-Peng; Jiang, Xunqing; Yamashita, Masahiro; Moriya, Tsuji; Tison, Christopher
Developing a safe and effective preventive for HIV-1 remains the hope for controlling the global AIDS epidemic. Recently, mRNA vaccines have emerged as a promising alternative to conventional vaccine approaches, primarily due to their rapid development and potential for low-cost manufacture. Despite the advantages of mRNA vaccines, challenges remain, especially due to the adverse effects of the delivery vehicle and low delivery efficiency. As a result, Luna Labs is developing a short carbon nanotube-based delivery platform (NanoVac) that can co-deliver mRNA and HIV-1 glycoproteins to the immune system efficiently with negligible toxicity. Surface chemistries of NanoVac were optimized to guide antigen/mRNA loading density and presentation. Multiple formulations were engineered for compatibility with both intramuscular and intranasal administration. NanoVac candidates demonstrated immunogenicity in rabbits and generated human-derived humoral and cellular responses in humanized mice (HIS). Briefly, 33% of the HIV-1-infected HIS mice vaccinated with NanoVac-mRNA was cleared of virus infection by 8-weeks post-infection. Finally, NanoVac stabilized the loaded mRNA against degradation under refrigeration for at least three months, reducing the cold chain burden for vaccine deployment.
PMCID:10377108
PMID: 37509124
ISSN: 2218-273x
CID: 5594262

Single-domain antibody-based noninvasive in vivo imaging of α-synuclein or tau pathology

Jiang, Yixiang; Lin, Yan; Krishnaswamy, Senthilkumar; Pan, Ruimin; Wu, Qian; Sandusky-Beltran, Leslie A; Liu, Mengyu; Kuo, Min-Hao; Kong, Xiang-Peng; Congdon, Erin E; Sigurdsson, Einar M
Intracellular deposition of α-synuclein and tau are hallmarks of synucleinopathies and tauopathies, respectively. Recently, several dye-based imaging probes with selectivity for tau aggregates have been developed, but suitable imaging biomarkers for synucleinopathies are still unavailable. Detection of both of these aggregates early in the disease process may allow for prophylactic therapies before functional impairments have manifested, highlighting the importance of developing specific imaging probes for these lesions. In contrast to the β sheet dyes, single-domain antibodies, found in camelids and a few other species, are highly specific, and their small size allows better brain entry and distribution than whole antibodies. Here, we have developed such imaging ligands via phage display libraries derived from llamas immunized with α-synuclein and tau preparations, respectively. These probes allow noninvasive and specific in vivo imaging of α-synuclein versus tau pathology in mice, with the brain signal correlating strongly with lesion burden. These small antibody derivatives have great potential for in vivo diagnosis of these diseases.
PMCID:10171817
PMID: 37163602
ISSN: 2375-2548
CID: 5476842

Vaccination with immune complexes modulates the elicitation of functional antibodies against HIV-1

Hioe, Catarina E; Liu, Xiaomei; Banin, Andrew N; Heindel, Daniel W; Klingler, Jéromine; Rao, Priyanka G; Luo, Christina C; Jiang, Xunqing; Pandey, Shilpi; Ordonez, Tracy; Barnette, Philip; Totrov, Maxim; Zhu, Jiang; Nádas, Arthur; Zolla-Pazner, Susan; Upadhyay, Chitra; Shen, Xiaoying; Kong, Xiang-Peng; Hessell, Ann J
INTRODUCTION:Neutralizing antibodies (Abs) are one of the immune components required to protect against viral infections. However, developing vaccines capable of eliciting neutralizing Abs effective against a broad array of HIV-1 isolates has been an arduous challenge. OBJECTIVE:This study sought to test vaccines aimed to induce Abs against neutralizing epitopes at the V1V2 apex of HIV-1 envelope (Env). METHODS:. RESULTS:Rabbit groups immunized with the DNA vaccine and uncomplexed or complexed UFO-BG.ΔV3 proteins (DNA/UFO-UC or IC) displayed similar profiles of Env- and V1V2-binding Abs but differed from the rabbits receiving the DNA vaccine and uncomplexed or complexed V1V2-2J9C proteins (DNA/V1V2-UC or IC), which generated more cross-reactive V1V2 Abs without detectable binding to gp120 or gp140 Env. Notably, the DNA/UFO-UC vaccine elicited neutralizing Abs against some heterologous tier 1 and tier 2 viruses from different clades, albeit at low titers and only in a fraction of animals, whereas the DNA/V1V2-UC or IC vaccines did not. In comparison with the DNA/UFO-UC group, the DNA/UFO-IC group showed a trend of higher neutralization against TH023.6 and a greater potency of V1V2-specific Ab-dependent cellular phagocytosis (ADCP) but failed to neutralize heterologous viruses. CONCLUSION:These data demonstrate the capacity of V1V2-2J9C-encoding DNA vaccine in combination with UFO-BG.ΔV3, but not V1V2-2J9C, protein vaccines, to elicit homologous and heterologous neutralizing activities in rabbits. The elicitation of neutralizing and ADCP activities was modulated by delivery of UFO-BG.ΔV3 complexed with V2i mAb 2158.
PMID: 37854587
ISSN: 1664-3224
CID: 5617942

Corrigendum: Vaccination with immune complexes modulates the elicitation of functional antibodies against HIV-1

Hioe, Catarina E; Liu, Xiaomei; Banin, Andrew N; Heindel, Daniel W; Klingler, Je Romine; Rao, Priyanka G; Luo, Christina C; Jiang, Xunqing; Pandey, Shilpi; Ordonez, Tracy; Barnette, Philip; Totrov, Maxim; Zhu, Jiang; Na das, Arthur; Zolla-Pazner, Susan; Upadhyay, Chitra; Shen, Xiaoying; Kong, Xiang-Peng; Hessell, Ann J
[This corrects the article DOI: 10.3389/fimmu.2023.1271686.].
PMID: 38022586
ISSN: 1664-3224
CID: 5617182

Engineered multivalent self-assembled binder protein against SARS-CoV-2 RBD

Britton, Dustin; Punia, Kamia; Mahmoudinobar, Farbod; Tada, Takuya; Jiang, Xunqing; Renfrew, P Douglas; Bonneau, Richard; Landau, Nathaniel R; Kong, Xiang-Peng; Montclare, Jin Kim
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic since December 2019, and with it, a push for innovations in rapid testing and neutralizing antibody treatments in an effort to solve the spread and fatality of the disease. One such solution to both of these prevailing issues is targeting the interaction of SARS-CoV-2 spike receptor binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2) receptor protein. Structural studies have shown that the N-terminal alpha-helix comprised of the first 23 residues of ACE2 plays an important role in this interaction. Where it is typical to design a binding domain to fit a target, we have engineered a protein that relies on multivalency rather than the sensitivity of a monomeric ligand to provide avidity to its target by fusing the N-terminal helix of ACE2 to the coiled-coil domain of the cartilage oligomeric matrix protein. The resulting ACE-MAP is able to bind to the SARS-CoV-2 RBD with improved binding affinity, is expressible in E. coli, and is thermally stable and relatively small (62 kDa). These properties suggest ACE-MAP and the MAP scaffold to be a promising route towards developing future diagnostics and therapeutics to SARS-CoV-2.
PMCID:9396458
PMID: 36034180
ISSN: 1369-703x
CID: 5337522