Journal articles on the topic 'Multivalent therapeutics'
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Farhadi, Shaheen A., and Gregory A. Hudalla. "Engineering galectin–glycan interactions for immunotherapy and immunomodulation." Experimental Biology and Medicine 241, no. 10 (May 2016): 1074–83. http://dx.doi.org/10.1177/1535370216650055.
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Galectins, a 15-member family of soluble carbohydrate-binding proteins, are receiving increasing interest as therapeutic targets for immunotherapy and immunomodulation due to their role as extracellular signals that regulate innate and adaptive immune cell phenotype and function. However, different galectins can have redundant, synergistic, or antagonistic signaling activity in normal immunological responses, such as resolution of inflammation and induction of antigen-specific tolerance. In addition, certain galectins can be hijacked to promote progression of immunopathologies, such as tumor immune privilege, metastasis, and viral infection, while others can inhibit these processes. Thus, eliciting a desired immunological outcome will likely necessitate therapeutics that can precisely enhance or inhibit particular galectin–glycan interactions. Multivalency is an important determinant of the affinity and specificity of natural galectin–glycan interactions, and is emerging as a key design element for therapeutics that can effectively manipulate galectin bioactivity. This minireview surveys current molecular and biomaterial engineering approaches to create therapeutics that can stabilize galectin multivalency or recapitulate natural glycan multivalency (i.e. “the glycocluster effect”). In particular, we highlight examples of using natural and engineered multivalent galectins for immunosuppression and immune tolerance, with a particular emphasis on treating autoimmune diseases or avoiding transplant rejection. In addition, we present examples of multivalent inhibitors of galectin–glycan interactions to maintain or restore T-cell function, with a particular emphasis on promoting antitumor immunity. Finally, we discuss emerging opportunities to further engineer galectin–glycan interactions for immunotherapy and immunomodulation.
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Lee, JuYeon, Yugang Bai, Ullas V. Chembazhi, Shaohong Peng, Kevin Yum, Long M. Luu, Lauren D. Hagler, et al. "Intrinsically cell-penetrating multivalent and multitargeting ligands for myotonic dystrophy type 1." Proceedings of the National Academy of Sciences 116, no. 18 (April 11, 2019): 8709–14. http://dx.doi.org/10.1073/pnas.1820827116.
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Developing highly active, multivalent ligands as therapeutic agents is challenging because of delivery issues, limited cell permeability, and toxicity. Here, we report intrinsically cell-penetrating multivalent ligands that target the trinucleotide repeat DNA and RNA in myotonic dystrophy type 1 (DM1), interrupting the disease progression in two ways. The oligomeric ligands are designed based on the repetitive structure of the target with recognition moieties alternating with bisamidinium groove binders to provide an amphiphilic and polycationic structure, mimicking cell-penetrating peptides. Multiple biological studies suggested the success of our multivalency strategy. The designed oligomers maintained cell permeability and exhibited no apparent toxicity both in cells and in mice at working concentrations. Furthermore, the oligomers showed important activities in DM1 cells and in a DM1 liver mouse model, reducing or eliminating prominent DM1 features. Phenotypic recovery of the climbing defect in adult DM1Drosophilawas also observed. This design strategy should be applicable to other repeat expansion diseases and more generally to DNA/RNA-targeted therapeutics.
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Force Aldred, Shelley, Andrew Boudreau, Ben Buelow, Starlynn Clarke, Kevin Dang, Laura Davison, Katherine Harris, et al. "Multispecific antibodies targeting CD38 show potent tumor-specific cytotoxicity." Journal of Clinical Oncology 36, no. 5_suppl (February 10, 2018): 57. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.57.
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57 Background: Multivalent antibodies targeting either CD38 alone or CD38 in conjunction with PD-L1 may yield therapeutics with superior biological activities and provide benefit for treating malignancies expressing low levels of CD38 (MCL, NHL, T cell lymphomas and Daratumumab refractory MM). Multivalent, multispecific antibodies kill CD38low cells through a variety of mechanisms including stronger and more specific engagement of CD38. Potent and directed immune checkpoint inhibition is realized by adding an anti-PD-L1 binding domain. Teneobio’s discovery platform utilizes VH domains (UniDabs) of fully human heavy chain antibodies (UniAbs) to develop bi-, tri-, and tetravalent antibodies. Methods: Individual UniDabs targeting CD38 and PDL1 were identified using our unique sequence-based discovery platform and high-throughput lead evaluation pipeline (TeneoSeek). This robust screening workflow enables evaluation of a large diversity of natural fully human antibodies, targeting multiple epitopes on a single antigen and uncovering important sequence activity relationships. UniDabs from transgenic rats are ideal building blocks for the generation of potent and highly manufacturable multivalent antibody therapeutics. Results: We have identified UniDabs that efficiently block PD-1/PD-L1 interaction as well as additional UniDabs that bind to five different functional epitopes on human CD38. Using different combinations and arrangements of UniDabs, a variety of multivalent antibodies were constructed and evaluated in in vitro models. Specific combinations of UniDabs show more potent cytotoxic effects than Daratumumab for multiple mechanisms including CDC and direct apoptosis. Conclusions: Data from a range of assay types show that multivalent UniAbs targeting CD38 can be engineered to display superior tumor cell cytotoxicity through multiple mechanisms of action.
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Chittasupho, Chuda, Teruna J. Siahaan, Charlotte M. Vines, and Cory Berkland. "Autoimmune therapies targeting costimulation and emerging trends in multivalent therapeutics." Therapeutic Delivery 2, no. 7 (July 2011): 873–89. http://dx.doi.org/10.4155/tde.11.60.
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Liu, S. P., L. Zhou, R. Lakshminarayanan, and R. W. Beuerman. "Multivalent Antimicrobial Peptides as Therapeutics: Design Principles and Structural Diversities." International Journal of Peptide Research and Therapeutics 16, no. 3 (August 26, 2010): 199–213. http://dx.doi.org/10.1007/s10989-010-9230-z.
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Rossi, Edmund A., David M. Goldenberg, Thomas M. Cardillo, Rhona Stein, Yang Wang, and Chien-Hsing Chang. "Novel Designs of Multivalent Anti-CD20 Humanized Antibodies as Improved Lymphoma Therapeutics." Cancer Research 68, no. 20 (October 15, 2008): 8384–92. http://dx.doi.org/10.1158/0008-5472.can-08-2033.
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Toretsky, Jeffrey A., and Peter E. Wright. "Assemblages: Functional units formed by cellular phase separation." Journal of Cell Biology 206, no. 5 (September 1, 2014): 579–88. http://dx.doi.org/10.1083/jcb.201404124.
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The partitioning of intracellular space beyond membrane-bound organelles can be achieved with collections of proteins that are multivalent or contain low-complexity, intrinsically disordered regions. These proteins can undergo a physical phase change to form functional granules or other entities within the cytoplasm or nucleoplasm that collectively we term “assemblage.” Intrinsically disordered proteins (IDPs) play an important role in forming a subset of cellular assemblages by promoting phase separation. Recent work points to an involvement of assemblages in disease states, indicating that intrinsic disorder and phase transitions should be considered in the development of therapeutics.
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Blanchard, Helen, Khuchtumur Bum-Erdene, and Matthew W. Hugo. "Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics." Australian Journal of Chemistry 67, no. 12 (2014): 1763. http://dx.doi.org/10.1071/ch14362.
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Galectins are a family of galactoside-specific lectins that are involved in a myriad of metabolic and disease processes. Due to roles in cancer and inflammatory and heart diseases, galectins are attractive targets for drug development. Over the last two decades, various strategies have been used to inhibit galectins, including polysaccharide-based therapeutics, multivalent display of saccharides, peptides, peptidomimetics, and saccharide-modifications. Primarily due to galectin carbohydrate binding sites having high sequence identities, the design and development of selective inhibitors targeting particular galectins, thereby addressing specific disease states, is challenging. Furthermore, the use of different inhibition assays by research groups has hindered systematic assessment of the relative selectivity and affinity of inhibitors. This review summarises the status of current inhibitors, strategies, and novel scaffolds that exploit subtle differences in galectin structures that, in conjunction with increasing available data on multiple galectins, is enabling the feasible design of effective and specific inhibitors of galectins.
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Miyashita, Shin-Ichiro, Jie Zhang, Sicai Zhang, Charles B. Shoemaker, and Min Dong. "Delivery of single-domain antibodies into neurons using a chimeric toxin–based platform is therapeutic in mouse models of botulism." Science Translational Medicine 13, no. 575 (January 6, 2021): eaaz4197. http://dx.doi.org/10.1126/scitranslmed.aaz4197.
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Efficient penetration of cell membranes and specific targeting of a cell type represent major challenges for developing therapeutics toward intracellular targets. One example facing these hurdles is to develop post-exposure treatment for botulinum neurotoxins (BoNTs), a group of bacterial toxins (BoNT/A to BoNT/G) that are major potential bioterrorism agents. BoNTs enter motor neurons, block neurotransmitter release, and cause a paralytic disease botulism. Members of BoNTs such as BoNT/A exhibit extremely long half-life within neurons, resulting in persistent paralysis for months, yet there are no therapeutics that can inhibit BoNTs once they enter neurons. Here, we developed a chimeric toxin–based delivery platform by fusing the receptor-binding domain of a BoNT, which targets neurons, with the membrane translocation domain and inactivated protease domain of the recently discovered BoNT-like toxin BoNT/X, which can deliver cargoes across endosomal membranes into the cytosol. A therapeutic protein was then created by fusing a single-domain antibody (nanobody) against BoNT/A with the delivery platform. In vitro characterization demonstrated that nanobodies were delivered into cultured neurons and neutralized BoNT/A in neurons. Administration of this protein in mice shortened duration of local muscle paralysis, restoring muscle function within hours, and rescued mice from systemic toxicity of lethal doses of BoNT/A. Fusion of two nanobodies, one against BoNT/A and the other against BoNT/B, created a multivalent therapeutic protein able to neutralize both BoNT/A and BoNT/B in mice. These studies provide an effective post-exposure treatment for botulism and establish a platform for intracellular delivery of therapeutics targeting cytosolic proteins and processes.
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Heitner, Tara, Noboru Satozawa, Kirk Mclean, David Vogel, Ronald R. Cobb, Bing Liu, Mithra Mahmoudi, et al. "Obligate Multivalent Recognition of Cell Surface Tomoregulin following Selection from a Multivalent Phage Antibody Library." Journal of Biomolecular Screening 11, no. 8 (December 2006): 985–95. http://dx.doi.org/10.1177/1087057106293841.
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A therapeutic antibody candidate (AT-19) isolated using multivalent phage display binds native tomoregulin (TR) as a mul-timer not as a monomer. This report raises the importance of screening and selecting phage antibodies on native antigen and reemphasizes the possibility that potentially valuable antibodies are discarded when a monomeric phage display system is used for screening. A detailed live cell panning selection and screening method to isolate multivalently active antibodies is described. AT-19 is a fully human antibody recognizing the cell surface protein TR, a proposed prostate cancer target for therapeutic antibody internalization. AT-19 was isolated from a multivalent single-chain variable fragment (scFv) antibody library rescued with hyperphage. The required multivalency for isolation of AT-19 is supported by fluorescence activated cell sorting data demonstrating binding of the multivalent AT-19 phage particles at high phage concentrations and failure of monovalent particles to bind. Pure monomeric scFv AT-19 does not bind native receptor on cells, whereas dimeric scFv or immunoglobulin G binds with nanomolar affinity. The isolation of AT-19 antibody with obligate bivalent binding activity to native TR is attributed to the use of a multivalent display of scFv on phage and the method for selecting and screening by alternate use of 2 recombinant cell lines.
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Gao, Rachel Y., Christine M. Riley, Evan Toth, Rebecca H. Blair, Megan N. Gerold, Caitlin McCormick, Amber W. Taylor, Tianjing Hu, Kathy L. Rowlen, and Erica D. Dawson. "Rapid Identity and Quantity CQA Test for Multivalent mRNA Drug Product Formulations." Vaccines 10, no. 10 (October 12, 2022): 1704. http://dx.doi.org/10.3390/vaccines10101704.
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The COVID-19 pandemic highlighted mRNA as a promising platform for vaccines and therapeutics. Many of the analytical tools used to characterize the critical quality attributes of mRNA are inherently singleplex and are not necessarily optimal from a labor and cost perspective. Here, we demonstrate the feasibility of a multiplexed platform (VaxArray) for efficient identity verification and concentration determination for both monovalent and multivalent mRNA formulations. A model system comprising mRNA constructs for influenza hemagglutinin and neuraminidase was used to characterize the analytical performance metrics for a VaxArray mRNA assay. The assay presented herein had a time to result of less than 2 h, required no PCR-based amplification nor extraction of mRNA from lipid nanoparticles, and exhibited high construct specificity that enabled application to the bivalent mixture. The sensitivity for influenza hemagglutinin and neuraminidase mRNA was sub-µg/mL, which is vaccine-relevant, and the average accuracy (%recovery of a check standard) and precision were 104 ± 2% and 9 ± 2%, respectively.
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Salih, Suliman, Ajnas Alkatheeri, Wijdan Alomaim, and Aisyah Elliyanti. "Radiopharmaceutical Treatments for Cancer Therapy, Radionuclides Characteristics, Applications, and Challenges." Molecules 27, no. 16 (August 16, 2022): 5231. http://dx.doi.org/10.3390/molecules27165231.
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Advances in the field of molecular biology have had an impact on biomedical applications, which provide greater hope for both imaging and therapeutics. Work has been intensified on the development of radionuclides and their application in radiopharmaceuticals (RPS) which will certainly influence and expand therapeutic approaches in the future treatment of patients. Alpha or beta particles and Auger electrons are used for therapy purposes, and each has advantages and disadvantages. The radionuclides labeled drug delivery system will deliver the particles to the specific targeting cell. Different radioligands can be chosen to uniquely target molecular receptors or intracellular components, making them suitable for personal patient-tailored therapy in modern cancer therapy management. Advances in nanotechnology have enabled nanoparticle drug delivery systems that can allow for specific multivalent attachment of targeted molecules of antibodies, peptides, or ligands to the surface of nanoparticles for therapy and imaging purposes. This review presents fundamental radionuclide properties with particular reference to tumor biology and receptor characteristic of radiopharmaceutical targeted therapy development.
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Marson, Domenico, Erik Laurini, Suzana Aulic, Maurizio Fermeglia, and Sabrina Pricl. "Evolution from Covalent to Self-Assembled PAMAM-Based Dendrimers as Nanovectors for siRNA Delivery in Cancer by Coupled In Silico-Experimental Studies. Part I: Covalent siRNA Nanocarriers." Pharmaceutics 11, no. 7 (July 18, 2019): 351. http://dx.doi.org/10.3390/pharmaceutics11070351.
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Small interfering RNAs (siRNAs) represent a new approach towards the inhibition of gene expression; as such, they have rapidly emerged as promising therapeutics for a plethora of important human pathologies including cancer, cardiovascular diseases, and other disorders of a genetic etiology. However, the clinical translation of RNA interference (RNAi) requires safe and efficient vectors for siRNA delivery into cells. Dendrimers are attractive nanovectors to serve this purpose, as they present a unique, well-defined architecture and exhibit cooperative and multivalent effects at the nanoscale. This short review presents a brief introduction to RNAi-based therapeutics, the advantages offered by dendrimers as siRNA nanocarriers, and the remarkable results we achieved with bio-inspired, structurally flexible covalent dendrimers. In the companion paper, we next report our recent efforts in designing, characterizing and testing a series of self-assembled amphiphilic dendrimers and their related structural alterations to achieve unprecedented efficient siRNA delivery both in vitro and in vivo.
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Brier, Livia, Amy A. Twite, Adam Barnebey, Mavish Mahomed, and Wesley M. Jackson. "Abstract 4157: Using a multivalent immunotherapy platform to extend intratumoral therapeutic durability." Cancer Research 82, no. 12_Supplement (June 15, 2022): 4157. http://dx.doi.org/10.1158/1538-7445.am2022-4157.
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Abstract Purpose: There is a critical need in immunotherapy drug development to enable focused and sustained immune cell modulation within a tumor to induce and propagate a system-wide anti-tumor response. We have developed a novel immunotherapy platform that could be used to generate geographically focused cancer cell growth inhibition or immune cell activation, thereby stimulating an anti-tumor immune response against primary solid tumors that can also travel to secondary metastases. Methods: Using published methods, we synthesized multivalent protein (MVP) conjugates by conjugating multiple copies (i.e. valency) of immune stimulating proteins, checkpoint inhibitors or anti-tumor antibodies to soluble, long-chain biopolymers. We verified that we can reproducibly generate MVP valencies ranging from 20-120 protein copies (±10%) per polymer backbone. We determined the binding affinity of these MVPs to their respective targets using biolayer interferometry and cell bioassays, and we measured the hydrodynamic radius of these immunotherapies using dynamic light scattering. Then, we injected fluorescently modified MVPs or their unconjugated counterparts directly into a variety of solid tumor models in mice. By taking longitudinal in vivo fluorescence measurements of the intratumoral (IT) drug signal over multiple days, we measured the IT half-life of each treatment. Results: Based on binding affinity measurements, we found that MVP potency increased directly with protein valency, and at high valency, the potency of MVPs were substantially greater than the unconjugated protein controls. Multivalent conjugation also increased the hydrodynamic radius of the MVPs to at least ten times larger than the unconjugated therapeutics. This large size was sufficient to slow the diffusion of MVP immunotherapies through dense tissues, such as solid tumors, as demonstrated by our in vivo studies. MVPs exhibited a higher IT drug signal with a more durable gradient within the tumor compared to the unconjugated controls, resulting in an extension of their IT half-lives by >5X in mouse solid tumors. Conclusions: The MVP platform can be used to modulate the potency and therapeutic durability for a wide range of immunotherapy targets. Further, the MVPs stay focused within the tumor after IT injection where they could generate a sustained anti-tumor immune response with minimal systemic exposure. Therefore, we expect MVP immunotherapies to have a better safety profile than IT or systemic delivery of an unconjugated therapeutic. We will continue to develop our internal MVP pipeline to finalize a candidate for IND-enabling studies. We are also seeking collaborations for co-development of additional immunotherapies that could benefit from the extended IT exposure and potency modulation enabled by the MVP platform. Citation Format: Livia Brier, Amy A. Twite, Adam Barnebey, Mavish Mahomed, Wesley M. Jackson. Using a multivalent immunotherapy platform to extend intratumoral therapeutic durability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4157.
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Sheikhi Mehrabadi, Fatemeh, Hanxiang Zeng, Mark Johnson, Cathleen Schlesener, Zhibin Guan, and Rainer Haag. "Multivalent dendritic polyglycerolamine with arginine and histidine end groups for efficient siRNA transfection." Beilstein Journal of Organic Chemistry 11 (May 13, 2015): 763–72. http://dx.doi.org/10.3762/bjoc.11.86.
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The success of siRNA-based therapeutics highly depends on a safe and efficient delivery of siRNA into the cytosol. In this study, we post-modified the primary amines on dendritic polyglycerolamine (dPG-NH2) with different ratios of two relevant amino acids, namely, arginine (Arg) and histidine (His). To investigate the effects from introducing Arg and His to dPG, the resulting polyplexes of amino acid functionalized dPG-NH2s (AAdPGs)/siRNA were evaluated regarding cytotoxicity, transfection efficiency, and cellular uptake. Among AAdPGs, an optimal vector with (1:3) Arg to His ratio, showed efficient siRNA transfection with minimal cytotoxicity (cell viability ≥ 90%) in NIH 3T3 cells line. We also demonstrated that the cytotoxicity of dPG-NH2 decreased as a result of amino acid functionalization. While the incorporation of both cationic (Arg) and pH-responsive residues (His) are important for safe and efficient siRNA transfection, this study indicates that AAdPGs containing higher degrees of His display lower cytotoxicity and more efficient endosomal escape.
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Mousavifar, Leila, and René Roy. "Design, Synthetic Strategies, and Therapeutic Applications of Heterofunctional Glycodendrimers." Molecules 26, no. 9 (April 22, 2021): 2428. http://dx.doi.org/10.3390/molecules26092428.
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Glycodendrimers have attracted considerable interest in the field of dendrimer sciences owing to their plethora of implications in biomedical applications. This is primarily due to the fact that cell surfaces expose a wide range of highly diversified glycan architectures varying by the nature of the sugars, their number, and their natural multiantennary structures. This particular situation has led to cancer cell metastasis, pathogen recognition and adhesion, and immune cell communications that are implicated in vaccine development. The diverse nature and complexity of multivalent carbohydrate–protein interactions have been the impetus toward the syntheses of glycodendrimers. Since their inception in 1993, chemical strategies toward glycodendrimers have constantly evolved into highly sophisticated methodologies. This review constitutes the first part of a series of papers dedicated to the design, synthesis, and biological applications of heterofunctional glycodendrimers. Herein, we highlight the most common synthetic approaches toward these complex molecular architectures and present modern applications in nanomolecular therapeutics and synthetic vaccines.
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Huang, Y.-J., A.-L. Shiau, S.-Y. Chen, Y.-L. Chen, C.-R. Wang, C.-Y. Tsai, M.-Y. Chang, Y.-T. Li, C.-H. Leu, and C.-L. Wu. "Multivalent structure of galectin-1-nanogold complex serves as potential therapeutics for rheumatoid arthritis by enhancing receptor clustering." European Cells and Materials 23 (March 13, 2012): 170–81. http://dx.doi.org/10.22203/ecm.v023a13.
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Kalathiya, Umesh, Monikaben Padariya, Robin Fahraeus, Soumyananda Chakraborti, and Ted R. Hupp. "Multivalent Display of SARS-CoV-2 Spike (RBD Domain) of COVID-19 to Nanomaterial, Protein Ferritin Nanocages." Biomolecules 11, no. 2 (February 17, 2021): 297. http://dx.doi.org/10.3390/biom11020297.
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SARS-CoV-2, or COVID-19, has a devastating effect on our society, both in terms of quality of life and death rates; hence, there is an urgent need for developing safe and effective therapeutics against SARS-CoV-2. The most promising strategy to fight against this deadly virus is to develop an effective vaccine. Internalization of SARS-CoV-2 into the human host cell mainly occurs through the binding of the coronavirus spike protein (a trimeric surface glycoprotein) to the human angiotensin-converting enzyme 2 (ACE2) receptor. The spike-ACE2 protein–protein interaction is mediated through the receptor-binding domain (RBD) of the spike protein. Mutations in the spike RBD can significantly alter interactions with the ACE2 host receptor. Due to its important role in virus transmission, the spike RBD is considered to be one of the key molecular targets for vaccine development. In this study, a spike RBD-based subunit vaccine was designed by utilizing a ferritin protein nanocage as a scaffold. Several fusion protein constructs were designed in silico by connecting the spike RBD via a synthetic linker (different sizes) to different ferritin subunits (H-ferritin and L-ferritin). The stability and the dynamics of the engineered nanocage constructs were tested by extensive molecular dynamics simulation (MDS). Based on our MDS analysis, a five amino acid-based short linker (S-Linker) was the most effective for displaying the spike RBD over the surface of ferritin. The behavior of the spike RBD binding regions from the designed chimeric nanocages with the ACE2 receptor was highlighted. These data propose an effective multivalent synthetic nanocage, which might form the basis for new vaccine therapeutics designed against viruses such as SARS-CoV-2.
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Majzoub, Ramsey N., Kai K. Ewert, and Cyrus R. Safinya. "Cationic liposome–nucleic acid nanoparticle assemblies with applications in gene delivery and gene silencing." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 374, no. 2072 (July 28, 2016): 20150129. http://dx.doi.org/10.1098/rsta.2015.0129.
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Cationic liposomes (CLs) are synthetic carriers of nucleic acids in gene delivery and gene silencing therapeutics. The introduction will describe the structures of distinct liquid crystalline phases of CL–nucleic acid complexes, which were revealed in earlier synchrotron small-angle X-ray scattering experiments. When mixed with plasmid DNA, CLs containing lipids with distinct shapes spontaneously undergo topological transitions into self-assembled lamellar, inverse hexagonal, and hexagonal CL–DNA phases. CLs containing cubic phase lipids are observed to readily mix with short interfering RNA (siRNA) molecules creating double gyroid CL–siRNA phases for gene silencing. Custom synthesis of multivalent lipids and a range of novel polyethylene glycol (PEG)-lipids with attached targeting ligands and hydrolysable moieties have led to functionalized equilibrium nanoparticles (NPs) optimized for cell targeting, uptake or endosomal escape. Very recent experiments are described with surface-functionalized PEGylated CL–DNA NPs, including fluorescence microscopy colocalization with members of the Rab family of GTPases, which directly reveal interactions with cell membranes and NP pathways. In vitro optimization of CL–DNA and CL–siRNA NPs with relevant primary cancer cells is expected to impact nucleic acid therapeutics in vivo . This article is part of the themed issue ‘Soft interfacial materials: from fundamentals to formulation’.
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Sun, Yaping, and Mitchell Ho. "Emerging antibody-based therapeutics against SARS-CoV-2 during the global pandemic." Antibody Therapeutics 3, no. 4 (November 24, 2020): 246–56. http://dx.doi.org/10.1093/abt/tbaa025.
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Abstract SARS-CoV-2 antibody therapeutics are being evaluated in clinical and preclinical stages. As of 11 October 2020, 13 human monoclonal antibodies targeting the SARS-CoV-2 spike protein have entered clinical trials with three (REGN-COV2, LY3819253/LY-CoV555, and VIR-7831/VIR-7832) in phase 3. On 9 November 2020, the US Food and Drug Administration issued an emergency use authorization for bamlanivimab (LY3819253/LY-CoV555) for the treatment of mild-to-moderate COVID-19. This review outlines the development of neutralizing antibodies against SARS-CoV-2, with a focus on discussing various antibody discovery strategies (animal immunization, phage display and B cell cloning), describing binding epitopes and comparing neutralizing activities. Broad-neutralizing antibodies targeting the spike proteins of SARS-CoV-2 and SARS-CoV might be helpful for treating COVID-19 and future infections. VIR-7831/7832 based on S309 is the only antibody in late clinical development, which can neutralize both SARS-CoV-2 and SARS-CoV although it does not directly block virus receptor binding. Thus far, the only cross-neutralizing antibody that is also a receptor binding blocker is nanobody VHH-72. The feasibility of developing nanobodies as inhaled drugs for treating COVID-19 and other respiratory diseases is an attractive idea that is worth exploring and testing. A cocktail strategy such as REGN-COV2, or engineered multivalent and multispecific molecules, combining two or more antibodies might improve the efficacy and protect against resistance due to virus escape mutants. Besides the receptor-binding domain, other viral antigens such as the S2 subunit of the spike protein and the viral attachment sites such as heparan sulfate proteoglycans that are on the host cells are worth investigating.
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Sadeghnezhad, Golnaz, Ema Romão, Robert Bernedo-Navarro, Sam Massa, Khosro Khajeh, Serge Muyldermans, and Sadegh Hassania. "Identification of New DR5 Agonistic Nanobodies and Generation of Multivalent Nanobody Constructs for Cancer Treatment." International Journal of Molecular Sciences 20, no. 19 (September 27, 2019): 4818. http://dx.doi.org/10.3390/ijms20194818.
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Current cancer therapeutics suffer from a lack of specificity in targeting tumor cells and cause severe side effects. Therefore, the design of highly specialized drugs comprising antibody derivatives inducing apoptosis in targeted cancer cells is considered to be a promising strategy. Drugs acting on death receptor 5 (DR5) such as DR5 agonist antibodies replacing “TNF-related apoptosis-inducing ligand” (TRAIL) offer feasible opportunities in this direction. Although such agonists provided good antitumor activity in preclinical studies, they were less effective in clinical studies, possibly due to a disturbed Fc interaction with Fc-γ receptors. Thus, multimerized antigen binding fragments without Fc have been proposed to increase their efficacy. We generated nanobodies (Nbs), recombinant variable domains of heavy chain-only antibodies of camelids, against the DR5 ectodomain. Nb24 and Nb28 had an affinity in the nM and sub-nM range, but only Nb28 competes with TRAIL for binding to DR5. Bivalent, trivalent, and tetravalent constructs were generated, as well as an innovative pentameric Nb complex, to provoke avidity effects. In our cellular assays, these trimeric, tetrameric, and pentameric Nbs have a higher apoptotic capacity than monomeric Nbs and seem to mimic the activity of the natural TRAIL ligand on various cancer cells.
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Iwasaki, Yasuhiko. "Bone Mineral Affinity of Polyphosphodiesters." Molecules 25, no. 3 (February 10, 2020): 758. http://dx.doi.org/10.3390/molecules25030758.
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Biomimetic molecular design is a promising approach for generating functional biomaterials such as cell membrane mimetic blood-compatible surfaces, mussel-inspired bioadhesives, and calcium phosphate cements for bone regeneration. Polyphosphoesters (PPEs) are candidate biomimetic polymer biomaterials that are of interest due to their biocompatibility, biodegradability, and structural similarity to nucleic acids. While studies on the synthesis of PPEs began in the 1970s, the scope of their use as biomaterials has increased in the last 20 years. One advantageous property of PPEs is their molecular diversity due to the presence of multivalent phosphorus in their backbones, which allows their physicochemical and biointerfacial properties to be easily controlled to produce the desired molecular platforms for functional biomaterials. Polyphosphodiesters (PPDEs) are analogs of PPEs that have recently attracted interest due to their strong affinity for biominerals. This review describes the fundamental properties of PPDEs and recent research in the field of macromolecular bone therapeutics.
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Laurini, Erik, Domenico Marson, Suzana Aulic, Maurizio Fermeglia, and Sabrina Pricl. "Evolution from Covalent to Self-Assembled PAMAM-Based Dendrimers as Nanovectors for siRNA Delivery in Cancer by Coupled in Silico-Experimental Studies. Part II: Self-Assembled siRNA Nanocarriers." Pharmaceutics 11, no. 7 (July 10, 2019): 324. http://dx.doi.org/10.3390/pharmaceutics11070324.
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In part I of this review, the authors showed how poly(amidoamine) (PAMAM)-based dendrimers can be considered as promising delivering platforms for siRNA therapeutics. This is by virtue of their precise and unique multivalent molecular architecture, characterized by uniform branching units and a plethora of surface groups amenable to effective siRNA binding and delivery to e.g., cancer cells. However, the successful clinical translation of dendrimer-based nanovectors requires considerable amounts of good manufacturing practice (GMP) compounds in order to conform to the guidelines recommended by the relevant authorizing agencies. Large-scale GMP-standard high-generation dendrimer production is technically very challenging. Therefore, in this second part of the review, the authors present the development of PAMAM-based amphiphilic dendrons, that are able to auto-organize themselves into nanosized micelles which ultimately outperform their covalent dendrimer counterparts in in vitro and in vivo gene silencing.
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Gillespie, James W., Liping Yang, Laura Maria De Plano, Murray A. Stackhouse, and Valery A. Petrenko. "Evolution of a Landscape Phage Library in a Mouse Xenograft Model of Human Breast Cancer." Viruses 11, no. 11 (October 26, 2019): 988. http://dx.doi.org/10.3390/v11110988.
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Peptide-displayed phage libraries are billion-clone collections of diverse chimeric bacteriophage particles, decorated by genetically fused peptides built from a random combination of natural amino acids. Studying the molecular evolution of peptide-displayed libraries in mammalian model systems, using in vivo phage display techniques, can provide invaluable knowledge about the underlying physiology of the vasculature system, allow recognition of organ- and tissue-specific networks of protein–protein interactions, and provide ligands for targeted diagnostics and therapeutics. Recently, we discovered that landscape phage libraries, a specific type of multivalent peptide phage display library, expose on their surface comprehensive collections of elementary binding units (EBUs), which can form short linear motifs (SLiMs) that interact with functional domains of physiologically relevant proteins. Because of their unique structural and functional features, landscape phages can use an alternative mechanism of directed molecular evolution, i.e., combinatorial avidity selection. These discoveries fueled our interest in revisiting the in vivo evolution of phage displayed libraries using another format of display, i.e., landscape phages. In this study, we monitored the evolution of a landscape phage library in a mouse model with and without an implanted human breast cancer tumor xenograft. As expected, the multivalent architecture of landscape phage displayed proteins provided strong tissue selectivity and resulted in a huge diversity of tissue penetrating, chimeric phage particles. We identified several types of EBU interactions that evolved during the course of tissue distribution, which included interactions of EBUs with all tissue types, those EBUs that interacted selectively with specific organs or tissues with shared gene expression profiles or functionalities, and other EBUs that interacted in a tissue-selective manner. We demonstrated that landscape phage libraries are a rich collection of unique nanobioparticles that can be used to identify functional organ and tissue-binding elements after the evolution of a phage display library in vivo.
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Rossi, Edmund A., David M. Goldenberg, Thomas M. Cardillo, Rhona Stein, and Chien-Hsing Chang. "Hexavalent bispecific antibodies represent a new class of anticancer therapeutics: 1. Properties of anti-CD20/CD22 antibodies in lymphoma." Blood 113, no. 24 (June 11, 2009): 6161–71. http://dx.doi.org/10.1182/blood-2008-10-187138.
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Abstract The dock and lock (DNL) method is a new technology for generating multivalent antibodies. Here, we report in vitro and in vivo characterizations of 20-22 and 22-20, a pair of humanized hexavalent anti-CD20/22 bispecific antibodies (bsAbs) derived from veltuzumab (v-mab) and epratuzumab (e-mab). The 22-20 was made by site-specific conjugation of e-mab to 4 Fabs of v-mab; 20-22 is of the opposite configuration, composing v-mab and 4 Fabs of e-mab. Each bsAb translocates both CD22 and CD20 into lipid rafts, induces apoptosis and growth inhibition without second-antibody crosslinking, and is significantly more potent in killing lymphoma cells in vitro than their parental antibodies. Although both bsAbs triggered antibody-dependent cellular toxicity, neither displayed complement-dependent cytotoxicity. Intriguingly, 22-20 and 20-22 killed human lymphoma cells in preference to normal B cells ex vivo, whereas the parental v-mab depleted malignant and normal B cells equally. In vivo studies in Daudi tumors revealed 20-22, despite having a shorter serum half-life, had antitumor efficacy comparable with equimolar v-mab; 22-20 was less potent than 20-22 but more effective than e-mab and control bsAbs. These results indicate multiple advantages of hexavalent anti-CD20/22 bsAbs over the individual parental antibodies and suggest that these may represent a new class of cancer therapeutics.
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Clua, Anna, Santiago Grijalvo, Namrata Erande, Swati Gupta, Kristina Yucius, Raimundo Gargallo, Stefania Mazzini, Muthiah Manoharan, and Ramon Eritja. "Properties of Parallel Tetramolecular G-Quadruplex Carrying N-Acetylgalactosamine as Potential Enhancer for Oligonucleotide Delivery to Hepatocytes." Molecules 27, no. 12 (June 20, 2022): 3944. http://dx.doi.org/10.3390/molecules27123944.
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The development of oligonucleotide conjugates for in vivo targeting is one of the most exciting areas for oligonucleotide therapeutics. A major breakthrough in this field was the development of multifunctional GalNAc-oligonucleotides with high affinity to asialoglycoprotein receptors (ASGPR) that directed therapeutic oligonucleotides to hepatocytes. In the present study, we explore the use of G-rich sequences functionalized with one unit of GalNAc at the 3′-end for the formation of tetrameric GalNAc nanostructures upon formation of a parallel G-quadruplex. These compounds are expected to facilitate the synthetic protocols by providing the multifunctionality needed for the binding to ASGPR. To this end, several G-rich oligonucleotides carrying a TGGGGGGT sequence at the 3′-end functionalized with one molecule of N-acetylgalactosamine (GalNAc) were synthesized together with appropriate control sequences. The formation of a self-assembled parallel G-quadruplex was confirmed through various biophysical techniques such as circular dichroism, nuclear magnetic resonance, polyacrylamide electrophoresis and denaturation curves. Binding experiments to ASGPR show that the size and the relative position of the therapeutic cargo are critical for the binding of these nanostructures. The biological properties of the resulting parallel G-quadruplex were evaluated demonstrating the absence of the toxicity in cell lines. The internalization preferences of GalNAc-quadruplexes to hepatic cells were also demonstrated as well as the enhancement of the luciferase inhibition using the luciferase assay in HepG2 cell lines versus HeLa cells. All together, we demonstrate that tetramerization of G-rich oligonucleotide is a novel and simple route to obtain the beneficial effects of multivalent N-acetylgalactosamine functionalization.
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Kupihár, Zoltán, Györgyi Ferenc, Vencel L. Petrovicz, Viktória R. Fáy, Lajos Kovács, Tamás A. Martinek, and Zsófia Hegedüs. "Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide Conjugates." Pharmaceutics 15, no. 1 (January 11, 2023): 248. http://dx.doi.org/10.3390/pharmaceutics15010248.
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Oligonucleotide conjugates are versatile scaffolds that can be applied in DNA-based screening platforms and ligand display or as therapeutics. Several different chemical approaches are available for functionalizing oligonucleotides, which are often carried out on the 5′ or 3′ end. Modifying oligonucleotides in the middle of the sequence opens the possibility to ligate the conjugates and create DNA strands bearing multiple different ligands. Our goal was to establish a complete workflow that can be applied for such purposes from monomer synthesis to templated ligation. To achieve this, a monomer is required with an orthogonal functional group that can be incorporated internally into the oligonucleotide sequence. This is followed by conjugation with different molecules and ligation with the help of a complementary template. Here, we show the synthesis and the application of a thiol-modified thymidine nucleoside phosphoramidite to prepare ligatable oligonucleotide conjugates. The conjugations were performed both in solution and on solid phase, resulting in conjugates that can be assembled into multivalent oligonucleotides decorated with tissue-targeting peptides using templated ligation.
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Gambles, M. Tommy, Jiahui Li, Jiawei Wang, Douglas Sborov, Jiyuan Yang, and Jindřich Kopeček. "Crosslinking of CD38 Receptors Triggers Apoptosis of Malignant B Cells." Molecules 26, no. 15 (July 31, 2021): 4658. http://dx.doi.org/10.3390/molecules26154658.
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Recently, we designed an inventive paradigm in nanomedicine—drug-free macromolecular therapeutics (DFMT). The ability of DFMT to induce apoptosis is based on biorecognition at cell surface, and crosslinking of receptors without the participation of low molecular weight drugs. The system is composed of two nanoconjugates: a bispecific engager, antibody or Fab’ fragment—morpholino oligonucleotide (MORF1) conjugate; the second nanoconjugate is a multivalent effector, human serum albumin (HSA) decorated with multiple copies of complementary MORF2. Here, we intend to demonstrate that DFMT is a platform that will be effective on other receptors than previously validated CD20. We appraised the impact of daratumumab (DARA)- and isatuximab (ISA)-based DFMT to crosslink CD38 receptors on CD38+ lymphoma (Raji, Daudi) and multiple myeloma cells (RPMI 8226, ANBL-6). The biological properties of DFMTs were determined by flow cytometry, confocal fluorescence microscopy, reactive oxygen species determination, lysosomal enlargement, homotypic cell adhesion, and the hybridization of nanoconjugates. The data revealed that the level of apoptosis induction correlated with CD38 expression, the nanoconjugates meet at the cell surface, mitochondrial signaling pathway is strongly involved, insertion of a flexible spacer in the structure of the macromolecular effector enhances apoptosis, and simultaneous crosslinking of CD38 and CD20 receptors increases apoptosis.
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Laird, Renee M., Christina L. Gariepy, Heather Eggleston, Nina M. Shoemaker, Mario A. Monteiro, Patricia Guerry, Zoltan Beck, Gary R. Matyas, and Frédéric Poly. "Application of a Campylobacter jejuni mouse infection model to test efficacy of a C. jejuni capsule conjugate vaccine delivered with a potent liposome adjuvant containing monophosphoryl lipid A and QS-21." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 168.20. http://dx.doi.org/10.4049/jimmunol.204.supp.168.20.
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Abstract Campylobacter jejuni is a major cause of infectious diarrhea worldwide. Increasing incidence of C. jejuni is attributed to new non-culture based detection methods and antibiotic resistance is unfortunately on the rise, necessitating development of interventions. Therapeutics development like vaccines have been hampered by lack of a small animal model that recapitulates campylobacteriosis symptoms. To better facilitate vaccine efficacy testing, we adapted a recently-published mouse C. jejuni infection model to adult mice fed a zinc-deficient diet and pre-treated with antibiotics prior to oral infection with C. jejuni strain 81–176. Non-vaccinated infected mice develop diarrhea, lose weight and show increased expression of fecal inflammatory markers indicating development of campylobacteriosis. We tested whether an 81–176 C. jejuni capsule conjugate vaccine delivered with a potent liposome adjuvant containing monophosphoryl lipid A and QS-21 known as ALFQ could protect mice against 81–176. Vaccinated mice developed high levels of anti-CPS IgG1 and IgG2b titers and serum bactericidal responses against 81–176. Vaccinated infected mice were protected against development of diarrhea, did not lose weight, and had significantly lower levels of fecal inflammatory marker expression. Importantly, vaccinated infected animals were protected against C. jejuni colonization indicating that parenteral vaccination with a conjugate vaccine plus the ALFQ adjuvant may provide protection against both C. jejuni disease and colonization. These promising results support further development of a multivalent C. jejuni conjugate vaccine platform delivered with potent adjuvant systems for use in human clinical studies.
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Nelissen, Frank H. T., Wenny J. M. Peeters, Timo P. Roelofs, Anika Nagelkerke, Paul N. Span, and Hans A. Heus. "Improving Breast Cancer Treatment Specificity Using Aptamers Obtained by 3D Cell-SELEX." Pharmaceuticals 14, no. 4 (April 9, 2021): 349. http://dx.doi.org/10.3390/ph14040349.
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Three-dimensional spheroids of non-malignant MCF10A and malignant SKBR3 breast cells were used for subsequent 3D Cell-SELEX to generate aptamers for specific binding and treatment of breast cancer cells. Using 3D Cell-SELEX combined with Next-Generation Sequencing and bioinformatics, ten abundant aptamer families with specific structures were identified that selectively bind to SKBR3, and not to MCF10A cells. Multivalent aptamer polymers were synthesized by co-polymerization and analyzed for binding performance as well as therapeutic efficacy. Binding performance was determined by confocal fluorescence imaging and revealed specific binding and efficient internalization of aptamer polymers into SKBR3 spheroids. For therapeutic purposes, DNA sequences that intercalate the cytotoxic drug doxorubicin were co-polymerized into the aptamer polymers. Viability tests show that the drug-loaded polymers are specific and effective in killing SKBR3 breast cancer cells. Thus, the 3D-selected aptamers enhanced the specificity of doxorubicin against malignant over non-malignant breast cells. The innovative modular DNA aptamer platform based on 3D Cell SELEX and polymer multivalency holds great promise for diagnostics and treatment of breast cancer.
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Wang, Jiawei, Lian Li, Jiyuan Yang, Phillip M. Clair, Martha Glenn, Deborah M. Stephens, D. Christopher Radford, et al. "Drug-Free Macromolecular Therapeutics Induce Apoptosis in Cells Isolated from Patients with B Cell Malignancies with Enhanced Apoptosis Induction By Pretreatment with Gemcitabine." Blood 132, Supplement 1 (November 29, 2018): 4426. http://dx.doi.org/10.1182/blood-2018-99-112001.
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Abstract Background Anti-CD20 mAbs are an important element in the therapeutic armamentarium for B-cell malignancies such as chronic lymphocytic leukemia (CLL). Although new targeted drugs (Ibrutinib & Idelalisib) and recently developed anti-CD20 mAbs (obinutuzumab & ofatumumab) have significant activity, the clinical management is limited by toxicity or low sensitivity to anti-CD20 mAbs. Herein we propose Drug-Free Macromolecular Therapeutics (DFMT) as a novel class of therapeutics that amplifies CD20 crosslinking and triggers apoptosis. The unique features of DFMT include augmentation of multivalent CD20 crosslinking, immune effector independence and no cytotoxic agents. Its effectiveness has been demonstrated in vitro and in preclinical Non-Hodgkin Lymphoma (NHL) models including a CD20-deficient rituximab (RTX)-resistant model, in which DFMT combined with a long-circulating polymer-gemcitabine conjugate (2P-GEM), induced prolonged survival and tumor clearance from bone marrows.[Zhang R, et al. PNAS 2014; Li L, et al. ACS Nano 2018] Therefore, we conducted assessment of DFMT on patient samples. Methods Malignant B cells were isolated from patients diagnosed by the hematologic malignancies service at the Huntsman Cancer Institute. The majority of isolates were from CLL patients. CD20 expression of each sample was evaluated by flow cytometry. DFMT consisting of two nanoconjugates was used to treat the cells in consecutive administration: first, cells were incubated with Fab'-MORF1 (bispecific engager, Fab' fragment of RTX conjugated with a morpholino oligonucleotide); after 1 h, a crosslinking effector (CLE) containing multiple copies of complementary morpholino oligonucleotide (MORF2) was added and the cells were continually incubated for another 6-20 h (depending on assays). The CLE can be prepared by conjugation of MORF2 to either N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer precursor or human serum albumin. Crosslinking of CD20 receptors is initiated by the multiple hybridization of MORF1/MORF2 at the cell surface, and results in apoptosis (Fig. 1A). Annexin V and caspase 3 assays were used to quantify B-cell apoptosis. RTX followed by goat-anti-human (GAH) secondary antibody was used for comparison. GAH was added to imitate the function of Fcγ+ immune effector cells for crosslinking of RTX. When enough cells were available, a detailed evaluation of apoptosis induction was performed, i.e. plasma membrane rupture, genomic DNA fragmentation, mitochondrial membrane permeabilization, Bcl-2 inhibition and confocal imaging to document specific biorecognition at the cell surface. In some samples, pretreatment with GEM or 2P-GEM for 48 hours followed by DFMT or RTX/GAH was conducted, and the effect of GEM in enhancing apoptosis induction was evaluated. Results The efficacy of DFMT was assessed in 44 samples including 35 CLL along with a few other B cell lymphomas such as diffuse large B cell lymphoma (DLBCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), etc. DFMT induced apoptosis in 65.9% of patient samples. High-risk mutations such as 17p13 and 11q22 deletions, usually considered as poor prognostic factors in CLL, did not hamper the therapeutic efficacy of DFMT treatment. In cases with poor responses, we noted low CD20 expression levels (Fig 1B). We previously showed that pre-treatment with GEM can enhance surface CD20 expression and restore responsiveness to anti-CD20 mAb. Therefore, we pre-treated the low CD20 patient samples with GEM followed by treatment of DFMT, which induced significantly more apoptosis than RTX/GAH control (Fig 1C). In addition to increased target expression (CD20), this superior activity is likely due to synergy between GEM and DFMT, as we have shown that CD20 crosslinking triggered by DFMT stimulates a cascade of apoptotic events that eventually lead to up-regulation of the pro-apoptotic proteins Bax and inhibition of NF-ĸB, which in turn sensitizes cells to GEM.[Li L, et al. ACS Nano 2018] Conclusion DFMT effectively increased apoptosis of tumor cells from patients with a variety of B-cell malignancies, irrespective of genomic aberrations. The apoptotic response to DFMT was significantly correlated with CD20 expression, and could be enhanced by GEM-induced upregulation of CD20. DFMT alone or in combination with 2P-GEM warrants further evaluation as a therapeutic for refractory B cell malignancies. Disclosures Yang: Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; University of Utah: Patents & Royalties: PCT/US2014/023784 and PCT/US2017/37736. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees. Kopeček:University of Utah: Patents & Royalties: PCT/US2014/023784 and PCT/US2017/37736; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees.
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Gardiner, John M. "The therapeutic potential of synthetic multivalent carbohydrates." Expert Opinion on Investigational Drugs 7, no. 3 (March 1998): 405–11. http://dx.doi.org/10.1517/13543784.7.3.405.
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Neill, Thomas, Liliana Schaefer, and Renato V. Iozzo. "Decorin as a multivalent therapeutic agent against cancer." Advanced Drug Delivery Reviews 97 (February 2016): 174–85. http://dx.doi.org/10.1016/j.addr.2015.10.016.
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Wang, Beatrice, Ling Wang, Tasnim Kothambawala, Susan Calhoun, Thomas Matthew, Genevive Hernandez, Marvin Peterson, Angus Sinclair, Eric William Humke, and Bruce Keyt. "IGM-8444 as a potent agonistic Death Receptor 5 (DR5) IgM antibody: Induction of tumor cytotoxicity, combination with chemotherapy and in vitro safety profile." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3595. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3595.
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3595 Background: Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF) receptor superfamily that multimerizes when bound to its ligand, TNF-related apoptosis inducing ligand (TRAIL), to activate the extrinsic apoptotic pathway. DR5 is broadly expressed on solid and hematologic cancers and has been targeted with both recombinant TRAIL and agonistic antibodies in the clinic. However, these therapeutics have generally been unsuccessful due to toxicity or lack of efficacy. We have developed a multivalent IgM DR5 agonist, IGM-8444, that multimerizes DR5 to selectively and potently induce tumor cell apoptosis while maintaining tolerability. Methods: IGM-8444 is an engineered, pentameric IgM antibody with 10 binding sites specific for DR5. Human tumor cell lines or hepatocytes were evaluated in vitro for dose dependent IGM-8444 induced cytotoxicity. The efficacy of IGM-8444 was evaluated with or without chemotherapy, in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse tumor models, with IGM-8444 administered at various dose levels and schedules when tumors reached approximately 100 mm3. Sera and tumors were analyzed for biomarkers of tumor apoptosis. Results: In vitro cytotoxicity assays identified IGM-8444 activity across cell lines from 18 solid and hematologic malignancies. In IGM-8444 partially resistant cell lines, combination with chemotherapy or a Bcl2 inhibitor enhanced in vitro cytotoxicity. IGM-8444 was efficacious as a monotherapy in CDX and PDX tumor models including colorectal, lung, and gastric indications. In a gastric PDX model, IGM-8444 induced complete and durable dose-dependent tumor regressions. In vivo, combination of IGM-8444 with standard-of-care chemotherapies, such as irinotecan, led to enhanced efficacy. IGM-8444 administration increased markers of tumor apoptosis, identifying potential clinical pharmacodynamic biomarkers. At doses several log-fold higher than efficacious doses, IGM-8444 demonstrated a favorable single agent in vitro safety profile, with little to no in vitro cytotoxicity observed using primary human hepatocytes from multiple donors. Conclusions: These data support the clinical development of IGM-8444 in both solid and hematological malignancies as a single agent and in combination with standard of care therapy. IGM-8444 is projected for IND filing in 2020.
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Zhao, Jisi, Shuang Li, Yingying Jin, Jessica Wang, Wenjing Li, Wenjie Wu, and Zhangyong Hong. "Multimerization Increases Tumor Enrichment of Peptide–Photosensitizer Conjugates." Molecules 24, no. 4 (February 25, 2019): 817. http://dx.doi.org/10.3390/molecules24040817.
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Photodynamic therapy (PDT) is an established therapeutic modality for the management of cancers. Conjugation with tumor-specific small molecule ligands (e.g., short peptides or peptidomimetics) could increase the tumor targeting of PDT agents, which is very important for improving the outcome of PDT. However, compared with antibody molecules, small molecule ligands have a much weaker affinity to their receptors, which means that their tumor enrichment is not always ideal. In this work, we synthesized multimeric RGD ligand-coupled conjugates of pyropheophorbide-a (Pyro) to increase the affinity through multivalent and cluster effects to improve the tumor enrichment of the conjugates. Thus, the dimeric and trimeric RGD peptide-coupled Pyro conjugates and the monomeric one for comparison were efficiently synthesized via a convergent strategy. A short polyethylene glycol spacer was introduced between two RGD motifs to increase the distance required for multivalence. A subsequent binding affinity assay verified the improvement of the binding towards integrin αvβ3 receptors after the increase in the valence, with an approximately 20-fold improvement in the binding affinity of the trimeric conjugate compared with that of the monomeric conjugate. In vivo experiments performed in tumor-bearing mice also confirmed a significant increase in the distribution of the conjugates in the tumor site via multimerization, in which the trimeric conjugate had the best tumor enrichment compared with the other two conjugates. These results indicated that the multivalence interaction can obviously increase the tumor enrichment of RGD peptide-conjugated Pyro photosensitizers, and the prepared trimeric conjugate can be used as a novel antitumor photodynamic agent with high tumor enrichment.
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Rossi, Edmund A., Chien-Hsing Chang, Thomas M. Cardillo, Rhona Stein, Diana Pilas, Diane L. Nordstrom, John Kopinski, and David M. Goldenberg. "Bispecific Anti-CD20/Anti-CD22 Antibodies with Potent Lymphoma Cytotoxicity." Blood 112, no. 11 (November 16, 2008): 1591. http://dx.doi.org/10.1182/blood.v112.11.1591.1591.
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Abstract BACKGROUND: Multivalent bispecific antibodies (bsMAbs) have shown improved efficacy in a number of preclinical studies. We made a pair of hexavalent bsMAbs based on epratuzumab (hLL2, anti-CD22) and veltuzumab (hA20, anti-CD20) by the Dock-and-Lock (DNL) method, and compared their properties to each other and their parental MAbs. METHODS AND RESULTS: DNL is used for the site-specific and covalent assembly of modular components, and was utilized to generate stably tethered hexavalent bispecific complexes, each composed of 4 Fab fragments conjugated to an IgG at the latter’s carboxyl termini of the heavy chain. DNL-1 has 4 veltuzumab Fabs tethered to epratuzumab IgG; DNL-2 has 4 epratuzumab Fabs bound to veltuzumab IgG. DNL made each construct as a single, defined, homogeneous structure that is stable in serum. All of the constituent Fab fragments are functional, with binding affinities similar to the parental MAbs. In vitro analyses using human lymphoma cell lines demonstrated that, unlike the parental MAbs, the bsMAbs each induced translocation of both CD22 and CD20 into lipid rafts and also strong cell-cell adhesion. DNL1 or DNL2 treatment resulted in increased apoptosis vs. the parental MAbs alone or combined. DNL1 and DNL2 inhibited the growth of Ramos, Raji and Daudi Burkitt lymphoma cell lines without the requirement of crosslinking, and more potently than the combination of the parental MAbs. For Daudi cells, DNL1 and DNL2 showed similar activity, which was approximately 50-fold more potent than the combination of the parental MAbs. For Raji and Ramos, DNL1 was 8–10-fold more potent than DNL2, which in turn was 8–10-fold more potent than the combined parental MAbs. The results suggest that crosslinking of CD20 and CD22 at the cell surface is required for enhanced cytotoxicity. Veltuzumab, but neither epratuzumab nor either bsMAb, displayed CDC activity. Veltuzumab and DNL2 induced a similarly high degree of ADCC. DNL1 induced ADCC to an intermediate level between veltuzumab/DNL2 and epratuzumab. In an ex-vivo assay using fresh whole blood mixed with either Daudi or Raji, DNL1 and DNL2 each demonstrated selective killing of lymphoma cells over normal B-cells compared to veltuzumab or rituximab; the latter depleted normal B-cells with greater efficiency than the bsMAbs. PK studies in mice demonstrated that despite their large size, the bsMAbs have a significantly shorter serum half-life than the IgGs. Even without CDC activity and with a considerably shorter serum half-life, DNL2 had anti-lymphoma efficacy in the Daudi Burkitt lymphoma model in mice that was equivalent to veltuzumab. DNL1 was less potent than DNL2 in vivo, but more effective than epratuzumab and control bsMAbs comprising either epratuzumab-IgG-AD2 (22-14) or 4 veltuzumab-Fab-DDD2 groups (734-22) combined with 4 non-binding Fab-DDD2 groups or a non-binding IgG-AD2, respectively. The anti-tumor efficacy of both DNL1 and DNL2 was abolished in tumor-bearing mice in which their ADCC potential was diminished by depletion of neutrophils and NK cells. These findings suggest that ADCC is the most critical mechanism of action for lymphoma killing in these murine models. DNL1 is more potent than DNL2 in vitro yet DNL2, having the stronger ADCC activity, is more potent than DNL1 in vivo. CONCLUSIONS: These findings suggest that the DNL method can be used to make a variety of multivalent bsMAbs with potent anti-tumor activity, and having distinct properties dependent on their arrangement and composition. CD20/CD22 bsMAbs appear to have different functions than their parental MAbs, even when these were combined, and appear to be potent anti-B-cell lymphoma therapeutics.
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Vorobyeva, Mariya, Pavel Vorobjev, and Alya Venyaminova. "Multivalent Aptamers: Versatile Tools for Diagnostic and Therapeutic Applications." Molecules 21, no. 12 (November 25, 2016): 1613. http://dx.doi.org/10.3390/molecules21121613.
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Chittasupho, Chuda. "Multivalent ligand: design principle for targeted therapeutic delivery approach." Therapeutic Delivery 3, no. 10 (October 2012): 1171–87. http://dx.doi.org/10.4155/tde.12.99.
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Riccardi, Claudia, Ettore Napolitano, Domenica Musumeci, and Daniela Montesarchio. "Dimeric and Multimeric DNA Aptamers for Highly Effective Protein Recognition." Molecules 25, no. 22 (November 10, 2020): 5227. http://dx.doi.org/10.3390/molecules25225227.
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Multivalent interactions frequently occur in biological systems and typically provide higher binding affinity and selectivity in target recognition than when only monovalent interactions are operative. Thus, taking inspiration by nature, bivalent or multivalent nucleic acid aptamers recognizing a specific biological target have been extensively studied in the last decades. Indeed, oligonucleotide-based aptamers are suitable building blocks for the development of highly efficient multivalent systems since they can be easily modified and assembled exploiting proper connecting linkers of different nature. Thus, substantial research efforts have been put in the construction of dimeric/multimeric versions of effective aptamers with various degrees of success in target binding affinity or therapeutic activity enhancement. The present review summarizes recent advances in the design and development of dimeric and multimeric DNA-based aptamers, including those forming G-quadruplex (G4) structures, recognizing different key proteins in relevant pathological processes. Most of the designed constructs have shown improved performance in terms of binding affinity or therapeutic activity as anti-inflammatory, antiviral, anticoagulant, and anticancer agents and their number is certainly bound to grow in the next future.
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Bartus, Éva, Gábor Olajos, Ildikó Schuster, Zsolt Bozsó, Mária Deli, Szilvia Veszelka, Fruzsina Walter, et al. "Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers." Molecules 23, no. 10 (October 2, 2018): 2523. http://dx.doi.org/10.3390/molecules23102523.
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Alzheimer’s disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event leading to the interruption of synapses and brain degeneration. Targeting neurotoxic Aβ oligomers can help recognize the disease at an early stage or it can be a potential therapeutic approach. Unnatural β-peptidic foldamers are successfully used against many different protein targets due to their favorable structural and pharmacokinetic properties compared to small molecule or protein-like drug candidates. We have previously reported a tetravalent foldamer-dendrimer conjugate which can selectively bind Aβ oligomers. Taking advantage of multivalency and foldamers, we synthesized different multivalent foldamer-based conjugates to optimize the geometry of the ligand. Isothermal titration calorimetry (ITC) was used to measure binding affinity to Aβ, thereafter 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based tissue viability assay and impedance-based viability assay on SH-SY5Y cells were applied to monitor Aβ toxicity and protective effects of the compounds. Important factors for high binding affinity were determined and a good correlation was found between influencing the valence and the capability of the conjugates for Aβ binding.
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Jana, Batakrishna, Dongkap Kim, Huyeon Choi, Minsoo Kim, Kibeom Kim, Sangpil Kim, Seongeon Jin, et al. "Drug resistance-free cytotoxic nanodrugs in composites for cancer therapy." Journal of Materials Chemistry B 9, no. 14 (2021): 3143–52. http://dx.doi.org/10.1039/d0tb02850a.
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A nanodrug as a macromolecular therapeutic agent was developed for addressing drug resistance in cancer therapy. The multivalent interactions between the nanodrugs and cytosolic components reflected their cytotoxicity.
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Mallikaratchy, Prabodhika, Alessandro Ruggiero, William Maguire, Kelly Piersanti, Jeffrey Gardner, Carlos Villa, Freddy Escorcia, et al. "Multivalent DNA Aptamer-Based Therapeutic Agents for Lymphoma and Leukemia." Blood 114, no. 22 (November 20, 2009): 2711. http://dx.doi.org/10.1182/blood.v114.22.2711.2711.
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Abstract Abstract 2711 Poster Board II-687 Non-Hodgkins lymphomas affect 450,000 patients in the United States and even with recent advances in antibody-based therapies; more than 20,000 people will die of their disease annually. The goal of this work was to develop a high affinity, stable aptamer selective for B-cell leukemias and lymphomas. Aptamers are small DNA molecules that have the ability to bind to proteins with high affinity and specificity. They are also ideal candidates as therapeutic carriers. Aptamer binding is based on the ability of small oligonucleotide polymers (typically 20–80mers) to fold into unique three-dimensional structures that can interact with a specific target. Based on nature of this interaction, aptamers could be considered to be antibody analogs. Compared to antibodies however, one of the inherent properties of aptamers is that their small size (typically 10–20,000 daltons for aptamers vs 150,000 daltons for antibodies,) might address some difficult pharmacologic issues of antibodies, which penetrate slowly into tumors and clear the blood slowly. Recently, the TDO5 aptamer was identified and it was found to bind to membrane bound human IgM, a component of the BCR complex in B-Cell neoplasms. In contrast to currently available monoclonal antibodies, TD05 binds to membrane bound human IgM only and not with soluble IgM, eliminating the possibility of competitive inhibition by soluble IgM in the serum. The specificity of the aptamer was confirmed by screening with 24 cell lines and fresh clinical leukemia samples. Out of 24 cell lines, the IgM-negative cells, including T-cell leukemias and solid tumor lines such as breast, kidney, and colon and ovarian, showed no binding with TD05 indicating there is no non-specific adhesion with cell lines. One of the challenges of using the current form of TD05 as a drug carrier is that it is not yet suitable for use in vivo because of low avidity (>10uM) and stability (t ½= 1min) at physiological conditions. In order to increase the affinity of this aptamer, a new truncated multivalent and nuclease stable aptamer was designed. First, truncation of the original version of TD05 was considered because reduced size may lead to more efficient chemical syntheses and better pharmacologic properties. The resulting TD05.1 has a 5-fold increased affinity compared to original version of TD05. Second, bivalent (BV) aptamers utilizing TD05.1 with various polyethylene glycol (PEG) linker lengths were designed. Linker length is critical in designing multivalent aptamers to avoid loss of binding due to steric hindrance and to optimize the binding geometry, both of which would affect binding affinity. An optimal linker length of ∼16nm was chosen after empiric binding studies. Nuclease stability was also addressed by the introduction of chemical functionalities into TD05.1. The introduction of non-natural bases such as LNA bases (Locked Nucleic Acids), have been demonstrated to be effective in this regard. The stability of LNA stems from the bicyclic furanose unit locked in a sugar conformation. In order to retain the specific recognition and 3-dimensional nature of the aptamer's folding, LNA analogues were only introduced at the regions that are not involved in binding. Additionally, to further improve nuclease resistance, increase circulation time in vivo and to prevent non-specific adhesion to serum proteins and cells, the LNA modified BV aptamer TD05.1 was modified with polyethylene glycol at the 3' and 5' ends. The introduction of LNA and polyethylene glycol further stabilized the secondary structure, increasing the affinity and nuclease resistance in serum from one minute to seven hours(t ½> 420 min). We then constructed a trivalent analog of the aptamer with multiple functionalities, including chelators and fluorophores, which showed ∼25-fold higher affinity compared to monomeric aptamer at physiological conditions. In conclusion, this study demonstrates the development of a trivalent, high affinity aptamer selective for the membrane bound human IgM found in B-cell leukemias and lymphoma. Studies to assess the biological activity and the use of this construct as a drug carrier to treat B-NHL and B-CLL are in progress. Disclosures: No relevant conflicts of interest to declare.
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Hall, Pamela R., Brian Hjelle, David C. Brown, Chunyan Ye, Virginie Bondu-Hawkins, Kathleen A. Kilpatrick, and Richard S. Larson. "Multivalent Presentation of Antihantavirus Peptides on Nanoparticles Enhances Infection Blockade." Antimicrobial Agents and Chemotherapy 52, no. 6 (April 7, 2008): 2079–88. http://dx.doi.org/10.1128/aac.01415-07.
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ABSTRACT Viral entry into susceptible host cells typically results from multivalent interactions between viral surface proteins and host entry receptors. In the case of Sin Nombre virus (SNV), a New World hantavirus that causes hantavirus cardiopulmonary syndrome, infection involves the interaction between viral membrane surface glycoproteins and the human integrin αvβ3. Currently, there are no therapeutic agents available which specifically target SNV. To address this problem, we used phage display selection of cyclic nonapeptides to identify peptides that bound SNV and specifically prevented SNV infection in vitro. We synthesized cyclic nonapeptides based on peptide sequences of phage demonstrating the strongest inhibition of infection, and in all cases, the isolated peptides were less effective at blocking infection (9.0% to 27.6% inhibition) than were the same peptides presented by phage (74.0% to 82.6% inhibition). Since peptides presented by the phage were pentavalent, we determined whether the identified peptides would show greater inhibition if presented in a multivalent format. We used carboxyl linkages to conjugate selected cyclic peptides to multivalent nanoparticles and tested infection inhibition. Two of the peptides, CLVRNLAWC and CQATTARNC, showed inhibition that was improved over that of the free format when presented on nanoparticles at a 4:1 nanoparticle-to-virus ratio (9.0% to 32.5% and 27.6% to 37.6%, respectively), with CQATTARNC inhibition surpassing 50% when nanoparticles were used at a 20:1 ratio versus virus. These data illustrate that multivalent inhibitors may disrupt polyvalent protein-protein interactions, such as those utilized for viral infection of host cells, and may represent a useful therapeutic approach.
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Popov, Jesse, Roger Gilabert-Oriol, and Marcel B. Bally. "Unique therapeutic properties and preparation methodology of multivalent rituximab-lipid nanoparticles." European Journal of Pharmaceutics and Biopharmaceutics 117 (August 2017): 256–69. http://dx.doi.org/10.1016/j.ejpb.2017.04.024.
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Sheard, Dean E., Wenyi Li, Neil M. O’Brien-Simpson, Frances Separovic, and John D. Wade. "Peptide Multimerization as Leads for Therapeutic Development." Biologics 2, no. 1 (December 30, 2021): 15–44. http://dx.doi.org/10.3390/biologics2010002.
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Multimerization of peptide structures has been a logical evolution in their development as potential therapeutic molecules. The multivalent properties of these assemblies have attracted much attention from researchers in the past and the development of more complex branching dendrimeric structures, with a wide array of biocompatible building blocks is revealing previously unseen properties and activities. These branching multimer and dendrimer structures can induce greater effect on cellular targets than monomeric forms and act as potent antimicrobials, potential vaccine alternatives and promising candidates in biomedical imaging and drug delivery applications. This review aims to outline the chemical synthetic innovations for the development of these highly complex structures and highlight the extensive capabilities of these molecules to rival those of natural biomolecules.
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Shah, Sachit, and Lorraine Leon. "Structural transitions and encapsulation selectivity of thermoresponsive polyelectrolyte complex micelles." Journal of Materials Chemistry B 7, no. 41 (2019): 6438–48. http://dx.doi.org/10.1039/c9tb01194c.
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Chiu, Gigi N. C., Lincoln A. Edwards, Anita I. Kapanen, Melina M. Malinen, Wieslawa H. Dragowska, Corinna Warburton, Ghania G. Chikh, et al. "Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs." Molecular Cancer Therapeutics 6, no. 3 (March 2007): 844–55. http://dx.doi.org/10.1158/1535-7163.mct-06-0159.
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Mistry, Hitesh, Fernando Ortega, Fernando Ortega, Johanna Lahdenranta, Punit Upadhyaya, Kristen Hurov, Phil Jeffrey, and Christophe Chassagnole. "826 Establishing the preclinical/translational PK/PD relationship for BT7480, a nectin-4/CD137 Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™)." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A865. http://dx.doi.org/10.1136/jitc-2021-sitc2021.826.
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BackgroundA new class of modular synthetic drugs, termed Bicycle tumor-targeted immune cell agonists (Bicycle TICAs), based on constrained bicyclic peptides has been developed as agonists of immune costimulatory receptors in cancer therapeutics.1 One example is BT7480 which binds simultaneously to Nectin-4 on tumor cells and CD137 on primed immune cells with activation (agonism) of CD137 being dependent on co-ligation of Nectin-4.MethodsIn vitro CD137 reporter activity and cytokine secretion data were generated using Bicycle TICAs including BT7480. These Bicycle TICAs could display a concentration-dependent activation (e.g. CD137 activation increases IFN-gamma production) reaching a maximal activity, which then decreases as the drug concentration increases.2 We developed a mathematical model to analyse this behaviour.We also modelled plasma and tumor pharmacokinetics of BT7480 in CT26-Nectin-4 tumor-bearing mice. A two-compartment model described the drug plasma profile after intravenous dosing and the tumor profile was described by a one effect compartment model. A tumor growth inhibition model for BT7480 was used to describe the preclinical data by placing the model within a mixed effect framework to estimate the population model parameters, i.e., tumor size at time 0 and tumor size growth rate, and to predict the parameter values for each mouse. We assessed how the tumor growth rate values correlate with the immune system markers collected.ResultsWe assessed the predictions of the in vitro model against the experimental observations and found that the position of the turning point could be predicted from the dissociation constants (Kd's). The combined BT7480 pharmacokinetic model shows that the elimination rate from plasma is faster than that from the tumor. We hypothesized that this results from BT7480 binding to Nectin-4 in the tumor. Also, we found that the level of tumor infiltrating CD8+ T-cells fully captures the treatment effect of BT7480 on tumor growth. Therefore, we established a likely causal link: from pharmacokinetic/dose to CD8+ T-cell infiltration changes and ultimately to tumor growth inhibition.ConclusionsA PK/PD modelling framework was developed that predicts preclinical biomarker level and tumor growth inhibition in response to changes in the BT7480 dose and dosing schedule. In addition, plasma and tumor drug concentration levels can be associated with the target concentration estimated using in vitro data.2 Namely, the product of the square-root of the two target Kds is likely to be the free drug concentration at which maximal activity of the trimer [T-Cell—BT7480—Tumor-Cell] is achieved.ReferencesUpadhyaya P. Anticancer immunity induced by a synthetic tumor-targeted CD137 agonist. Journal for ImmunoTherapy of Cancer 2021;9:e001762.Perelson AS. Receptor clustering on a cell surface. III. theory of receptor cross-linking by multivalent ligands: description by ligand states. Mathematical Biosciences 1981;53:1–39.
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Manenkov, P. "On the treatment of puerperal sepsis by local interstitial vaccination. Spirit o (Zbl. F. Gyn., 1933, no. 33)." Kazan medical journal 29, no. 11-12 (January 12, 2022): 989. http://dx.doi.org/10.17816/kazmj90308.
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On the treatment of puerperal sepsis by local interstitial vaccination. Spirit about (Zbl. F. Gyn., 1933, No. 33) considers a good therapeutic method - repeated injections, every 3 days, deep into the parenchyma of the vaginal part of 1/3 cc. sant. multivalent vaccine (streptococci 1 billion, staphylococci and gonococci 500 million each and Escherichia coli 300 million in 1 cc).
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Tan, Zhixin Cyrillus, Brian T. Orcutt-Jahns, and Aaron S. Meyer. "A quantitative view of strategies to engineer cell-selective ligand binding." Integrative Biology 13, no. 11 (November 2021): 269–82. http://dx.doi.org/10.1093/intbio/zyab019.
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Abstract A critical property of many therapies is their selective binding to target populations. Exceptional specificity can arise from high-affinity binding to surface targets expressed exclusively on target cell types. In many cases, however, therapeutic targets are only expressed at subtly different levels relative to off-target cells. More complex binding strategies have been developed to overcome this limitation, including multi-specific and multivalent molecules, creating a combinatorial explosion of design possibilities. Guiding strategies for developing cell-specific binding are critical to employ these tools. Here, we employ a uniquely general multivalent binding model to dissect multi-ligand and multi-receptor interactions. This model allows us to analyze and explore a series of mechanisms to engineer cell selectivity, including mixtures of molecules, affinity adjustments, valency changes, multi-specific molecules and ligand competition. Each of these strategies can optimize selectivity in distinct cases, leading to enhanced selectivity when employed together. The proposed model, therefore, provides a comprehensive toolkit for the model-driven design of selectively binding therapies.