Delivery Of Therapeutic Antibodies Research Articles

Subcellular trafficking and transcytosis efficacy of different receptor types for therapeutic antibody delivery at the blood‒brain barrier

Here, we report an experimental setup to benchmark different receptors for targeted therapeutic antibody delivery at the blood–brain barrier. We used brain capillary endothelial-like cells derived from induced pluripotent stem cells (hiPSC-BECs) as a model system and compared them to colon epithelial Caco-2 cells. This approach helped to identify favourable receptors for transport into the cell layer itself or for directing transport for transcytosis across the cell layer. The sorting receptors transferrin receptor and sortilin were shown to be efficient as antibody cargo receptors for intracellular delivery to the cell layer. In contrast, the cell surface receptors CD133 and podocalyxin were identified as static and inefficient receptors for delivering cargo antibodies. Similar to in vivo studies, the hiPSC-BECs maintained detectable transcytotic transport via transferrin receptor, while transcytosis was restricted using sortilin as a cargo receptor. Based on these findings, we propose the application of sortilin as a cargo receptor for delivering therapeutic antibodies into the brain microvascular endothelium.Graphical

Controlled release of therapeutic antibody using hydrolytically degradable microgels.

Monoclonal antibodies have gained significant interest as potential therapeutics for treating various diseases. However, these therapies are not always effective due to poor treatment compliance associated with multiple administrations and drug resistance. Thus, there is a growing interest in developing advanced monoclonal antibody delivery systems that can customize pharmacokinetics to enhance therapeutic outcomes. This work aimed to engineer hydrolytic 4-arm PEG maleimide (PEG-4MAL) microgels for the controlled delivery of therapeutic antibodies, specifically anti-angiogenic bevacizumab, to overcome the limitations of current monoclonal antibody therapies. Through a PEGylation reaction with a thiol-terminated PEG linker, the antibody was covalently conjugated to the macromer backbone before microgel synthesis. The PEGylation reaction was simple, effective, and did not affect antibody bioactivity. Antibody release kinetics was tuned by changing the concentration of the hydrolytic linker (0-2 mM) and/or PEG-4MAL:protein molar ratio (1000:1, 2000:1, and 5000:1) in the macromer precursor solution during microgel fabrication. The bioactivity of the released antibody was assessed on human umbilical endothelial vascular cells (HUVEC), demonstrating that extracts from hydrolytic microgels reduced cell proliferation over time. Collectively, this study demonstrates the development of highly tunable delivery platform based on degradable PEG-4MAL microgels that can be adapted for therapeutic antibody-controlled release.

Site-oriented conjugation of poly(2-methacryloyloxyethyl phosphorylcholine) for enhanced brain delivery of antibody.

Antibody therapeutics are limited in treating brain diseases due to poor blood-brain barrier (BBB) penetration. We have discovered that poly 2-methacryloyloxyethyl phosphorylcholine (PMPC), a biocompatible polymer, effectively facilitates BBB penetration via receptor-mediated transcytosis and have developed a PMPC-shell-based platform for brain delivery of therapeutic antibodies, termed nanocapsule. Yet, the platform results in functional loss of antibodies due to epitope masking by the PMPC polymer network, which necessitates the incorporation of a targeting moiety and degradable crosslinker to enable on-site antibody release. In this study, we developed a novel platform based on site-oriented conjugation of PMPC to the antibody, allowing it to maintain key functionalities of the original antibody. With an optimized PMPC chain length, the PMPC-antibody conjugate exhibited enhanced brain delivery while retaining epitope recognition, cellular internalization, and antibody-dependent cellular phagocytic activity. This simple formula incorporates only the antibody and PMPC without requiring additional components, thereby addressing the issues of the nanocapsule platform and paving the way for PMPC-based brain delivery strategies for antibodies.

Advancements in neural system bioengineering: precision therapeutics and innovative strategies

This literature review delves into innovative approaches in the realm of neural system bioengineering and their therapeutic implications. The authors address the interplay of contemporary bioengineering strategies, such as 3D bioprinting and biomaterial utilization, in the context of analyzing intricate neurological disorders and cellular interactions. The article presents an overview of precise treatment methodologies employing engineered exosomes capable of delivering therapeutic payloads to specific intracellular locations. The authors explore the prospects of applying engineered exosomes in personalized medicine and their integration with biomaterials and organoids for enhanced efficacy in treating neurological conditions. A pivotal question in neurological bioengineering pertains to overcoming the blood-brain barrier. The article scrutinizes the paradigm of antibody transcytosis, enabling the targeted delivery of therapeutic antibodies to sites of brain pathology. The authors also raise considerations about the role of nanoparticles and biomaterials within this context. Additionally, the paper provides an appraisal of biomaterials capable of mimicking brain tissue architecture and promoting tissue regeneration. The authors also discuss the evolution of brain organoid technology and its contributions to disease investigation and the formulation of therapeutic strategies. In conclusion, the article encapsulates the current status of neurological bioengineering, emphasizing the significance of precise therapeutic modalities and the interplay of biomaterials and technological innovations. Research findings delineate avenues for the development of innovative treatment approaches for neurological disorders and the more effective incorporation of bioengineering in medical practice.

Nogo-A antibody delivery through the olfactory mucosa mitigates experimental autoimmune encephalomyelitis in the mouse CNS

Systemic administration of Nogo-A-neutralizing antibody ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, the blood-brain barrier (BBB) is a major obstacle limiting the passage of systemically applied antibody to the CNS. To bypass the BBB, in the present study we tested the intranasal route of administration by targeting the olfactory mucosa with the Nogo-A-blocking antibody 11C7 mAb in myelin oligodendrocyte glycoprotein-induced EAE. Antibodies were specifically administered onto the olfactory mucosa using a microcatheter. Antibody distribution was examined in the CNS by ELISA and light-sheet microscopy. The effects of 11C7 mAb on Nogo-A signaling were assessed by Western blotting. EAE-induced deficits were monitored daily. Demyelination was observed on spinal cord histological sections. Gene expression changes were followed by trancriptomic analyses. A sensitive capture ELISA revealed a rapid and widespread distribution of 11C7 mAb in the CNS, including the olfactory bulb, the cerebellum and the lumbar spinal cord, but not in the CSF. Light-sheet microscopy allowed to observe antibody accumulation in the parenchyma, thus demonstrating nose-to-brain transfer of IgG. At the functional level, the widespread penetration of 11C7 mAb in the CNS, including the thoracolumbar spinal cord, resulted in the improvement of motor symptoms and in the preservation of myelin in the spinal cord of EAE mice. This was accompanied by Nogo-A signaling downregulation, as reflected by the decreased level of phosphorylated cofilin observed by Western blotting in the cerebellum. In the brain of EAE score-matched animals, 11C7 modified the expression of genes that can influence neurotransmission and cognitive functions, independently of the demyelination phenotype in the spinal cord. In conclusion, our data show the feasibility of olfactory mucosa-directed administration for the delivery of therapeutic antibodies targeting CNS antigens in EAE mice.

Aerosolization Performance of Immunoglobulin G by Jet and Mesh Nebulizers

Recently, many preclinical and clinical studies have been conducted on the delivery of therapeutic antibodies to the lungs using nebulizers, but standard treatment guidelines have not yet been established. Our objective was to compare nebulization performance according to the low temperature and concentration of immunoglobulin G (IgG) solutions in different types of nebulizers, and to evaluate the stability of IgG aerosols and the amount delivered to the lungs. The output rate of the mesh nebulizers decreased according to the low temperature and high concentration of IgG solution, whereas the jet nebulizer was unaffected by the temperature and concentration of IgG. An impedance change of the piezoelectric vibrating element in the mesh nebulizers was observed because of the lower temperature and higher viscosity of IgG solution. This affected the resonance frequency of the piezoelectric element and lowered the output rate of the mesh nebulizers. Aggregation assays using a fluorescent probe revealed aggregates in IgG aerosols from all nebulizers. The delivered dose of IgG to the lungs in mice was highest at 95 ng/mL in the jet nebulizer with the smallest droplet size. Evaluation of the performance of IgG solution delivered to the lungs by three types of nebulizers could provide valuable parameter information for determination on dose of therapeutic antibody by nebulizers.Graphical abstract

Improved Therapeutic Delivery Targeting Clinically Relevant Orthotopic Human Pancreatic Tumors Engrafted in Immunocompromised Pigs Using Ultrasound-Induced Cavitation: A Pilot Study.

Pancreatic tumors can be resistant to drug penetration due to high interstitial fluid pressure, dense stroma, and disarrayed vasculature. Ultrasound-induced cavitation is an emerging technology that may overcome many of these limitations. Low-intensity ultrasound, coupled with co-administered cavitation nuclei consisting of gas-stabilizing sub-micron scale SonoTran Particles, is effective at increasing therapeutic antibody delivery to xenograft flank tumors in mouse models. Here, we sought to evaluate the effectiveness of this approach in situ using a large animal model that mimics human pancreatic cancer patients. Immunocompromised pigs were surgically engrafted with human Panc-1 pancreatic ductal adenocarcinoma (PDAC) tumors in targeted regions of the pancreas. These tumors were found to recapitulate many features of human PDAC tumors. Animals were intravenously injected with the common cancer therapeutics Cetuximab, gemcitabine, and paclitaxel, followed by infusion with SonoTran Particles. Select tumors in each animal were targeted with focused ultrasound to induce cavitation. Cavitation increased the intra-tumor concentrations of Cetuximab, gemcitabine, and paclitaxel by 477%, 148%, and 193%, respectively, compared to tumors that were not targeted with ultrasound in the same animals. Together, these data show that ultrasound-mediated cavitation, when delivered in combination with gas-entrapping particles, improves therapeutic delivery in pancreatic tumors under clinically relevant conditions.

Oral Delivery of Therapeutic Antibodies with a Transmucosal Polymeric Carrier.

Therapeutic proteins are playing increasingly important roles in treating numerous types of diseases. However, oral administration of proteins, especially large ones (e.g., antibodies), remains a great challenge due to their difficulties in penetrating intestinal barriers. Herein, fluorocarbon-modified chitosan (FCS) is developed for efficient oral delivery of different therapeutic proteins, in particular large ones such as immune checkpoint blockade antibodies. In our design, therapeutic proteins are mixed with FCS to form nanoparticles, lyophilized with appropriate excipients, and then filled into enteric capsules for oral administration. It has been found that FCS could promote transmucosal delivery of its cargo protein via inducing transitory rearrangement of tight junction associated proteins between intestinal epithelial cells and subsequently release free proteins into blood circulation. It is shown that at a 5-fold dose oral delivery of anti-programmed cell death protein-1 (αPD1) or its combination with anti-cytotoxic T-lymphocyte antigen 4 (αCTLA4) using this method could achieve comparable antitumor therapeutic responses to that achieved by intravenous injection of corresponding free antibodies in various types of tumor models and, more excitingly, result in significantly reduced immune-related adverse events. Our work successfully demonstrates the enhanced oral delivery of antibody drugs to achieve systemic therapeutic responses and may revolutionize the future clinical usage of protein therapeutics.

COLON TARGETED DELIVERY AND STABILIZATION OF MONOCLONAL ANTIBODIES FOR LOCAL TREATMENT OF INFLAMMATORY BOWEL DISEASES

Abstract In the era of biologics where IBD treatment has been transformed by potent antibody-based therapeutics, a key challenge still remains, to develop orally administered antibody medicines for chronic GI inflammation. This is primarily due to the challenges in accurate oral targeted delivery of drugs to the lower GI tract and the inherent enzymatic instability of antibodies in these harsh luminal environment. As a result, all antibody therapeutics in clinical development and on the market are available only as an injection leading to undesired adverse effects due to high systemic exposure and suboptimal therapeutic response due to insufficient antibody levels at the inflamed tissue. We have developed a suite of delivery technologies that are designed to bypass the harsher stomach and small intestinal conditions of the GI tract and achieve accurate targeted release and enzymatic stabilization of the antibody therapeutics in the colon. The delivery platform comprises of a film coating which is applied on the outside of the pill. The coating is a clinically validated polymer coating comprising of a combination of pH sensitive polymer and polysaccharide that is designed to start releasing drugs only when exposed to the correct pH and/or colonic bacteria, dramatically improving on the inconsistent colonic release profiles of solely pH-based coatings. The second component is in the core of the pill, a cocktail of amino acid-based excipients that are mixed together with the antibody and protects the drug from pancreatic and bacterial origin protease enzymes, allowing high luminal antibody concentration build-up that leads to inflamed tissue/systemic uptake through a combination of active and passive diffusion. We demonstrated in an acute DSS mouse model of colitis the effective colonic delivery and stabilization of an anti-IL6 antibody leading to superior uptake into the tissue compared IP injection. The superior tissue level demonstrated higher downregulation of target IL6. We are working to leverage the delivery technology for oral delivery of a variety of anti-inflammatory and epithelial wound healing protein modalities such as monoclonal antibodies, fusion proteins, cytokines, VHHs and peptides to allow for broad therapeutic interventions in indications such as Crohn’s disease, ulcerative colitis, pouchitis and celiac disease. Mechanism of oral colon targeted delivery of therapeutic antibodies in local treatment of inflammatory bowel disease. In-vivo PK of anti-IL6 antibody in acute DSS colitis mouse model. A. Impact of stabilization on antibody levels in the colon lumen compared to naked antibody and injected antibody. B. Impact of stabilization on colon tissue uptake. C. Effect of tissue conc. on colon tissue IL6 target downregulation.

Development of an Antibody Delivery Method for Cancer Treatment by Combining Ultrasound with Therapeutic Antibody-Modified Nanobubbles Using Fc-Binding Polypeptide

A key challenge in treating solid tumors is that the tumor microenvironment often inhibits the penetration of therapeutic antibodies into the tumor, leading to reduced therapeutic efficiency. It has been reported that the combination of ultrasound-responsive micro/nanobubble and therapeutic ultrasound (TUS) enhances the tissue permeability and increases the efficiency of delivery of macromolecular drugs to target tissues. In this study, to facilitate efficient therapeutic antibody delivery to tumors using this combination system, we developed therapeutic antibody-modified nanobubble (NBs) using an Fc-binding polypeptide that can quickly load antibodies to nanocarriers; since the polypeptide was derived from Protein G. TUS exposure to this Herceptin®-modified NBs (Her-NBs) was followed by evaluation of the antibody's own ADCC activity, resulting the retained activity. Moreover, the utility of combining therapeutic antibody-modified NBs and TUS exposure as an antibody delivery system for cancer therapy was assessed in vivo. The Her-NBs + TUS group had a higher inhibitory effect than the Herceptin and Her-NBs groups. Overall, these results suggest that the combination of therapeutic antibody-modified NBs and TUS exposure can enable efficient antibody drug delivery to tumors, while retaining the original antibody activity. Hence, this system has the potential to maximize the therapeutic effects in antibody therapy for solid cancers.

The Use of Adeno-associated virus (AAV) in Vaccine Development


 Adeno-associated virus (AAV) is a very tiny (20-26 nm) icosahedral and non-enveloped virus, and it belongs to the Parvoviridae family. AAV vectors are the most widely used option for gene therapy and delivery of therapeutic antibodies due to their relatively low immunogenicity, high safety profile, broad tropism, and their tendency to maintain long-term gene expression [1]. AVV vectors are developed by transfection of human embryonic kidney (HEK) 293 T cells with transgene, packaging and helper plasmids [2]. Several clinical studies have investigated the use of AAV vectors for gene therapy in treating of Parkinson’s disease, Alzheimer’s disease, heart disease, and prostate cancer [3]. AAV vectors have previously been used to treat muscular diseases, but in recent years, their usage as vaccine vectors to cure or prevent infectious diseases including HIV, HPV, and influenza has expanded [4].
 
 Here, we discuss the advantages and disadvantages of the use of AAV in vaccine development, and future approaches in improving the drawbacks caused by AAV-based vaccines. Numerous animal investigations have been conducted to explore vaccine vectors against various illnesses, suggesting a possibility for AAV-based vaccinations. Clinical studies on humans are, however, uncommon because, in contrast to other viral vectors, AAV induces a poor humoral and cellular immune response. Additionally, infectious vaccinations often target a large group of healthy individuals across a variety of ages, including children and teenagers. Therefore, compared to AAV-based gene therapies, vaccinations based on AAV vectors need to be more cost-effective and need more robust safety control.
 
 According to several research, AAV vector vaccines have been shown to induce a stronger or longer lasting antibody response in comparison to other vaccination approaches, such as DNA, recombinant proteins, inactivated viruses, or virus-like particles (VLPs) [5]. However, AAV vectors are thought to have a low immunogenic profile in comparison to other viral vectors. The main limitations of AAV vectors are their low transgenic capacity and widespread pre-existing immunity in humans [6]. Currently, strategies for improving AAV immunogenicity and circumventing pre-existing immunity are actively being investigated. The research undertaken so far have highlighted numerous significant benefits of AAV vectors for immunisation. Despite all the advantages, there are still a variety of challenges that limit the use of these vectors as a vaccine in humans. Thus, it is necessary to overcome these challenges in order to make AAV-based vaccines effective.

Site-selective oral delivery of therapeutic antibodies to the inflamed colon via a folic acid-grafted organic/inorganic hybrid nanocomposite system.

This study aimed to develop a pH-responsive folic acid-grafted organic/inorganic hybrid nanocomposite system for site-selective oral delivery of therapeutic antibodies. A folic acid-grafted aminoclay (FA-AC) was prepared via an in situ sol‒gel method. Then, a drug-loaded nanocomplex was prepared via the electrostatic interaction of FA-AC with infliximab (IFX), a model antibody, and coated with Eudragit® S100 (EFA-AC-IFX). FA-AC exhibited favorable profiles as a drug carrier including low cytotoxicity, good target selectivity, and capability to form a nanocomplex with negatively charged macromolecules. A pH-responsive FA-AC-based nanocomplex containing IFX (EFA-AC-IFX) was also obtained in a narrow size distribution with high entrapment efficiency (>87%). The conformational stability of IFX entrapped in EFA-AC-IFX was well maintained in the presence of proteolytic enzymes. EFA-AC-IFX exhibited pH-dependent drug release, minimizing premature drug release in gastric conditions and the upper intestine. Accordingly, oral administration of EFA-AC-IFX to colitis-induced mice was effective in alleviating the progression of ulcerative colitis, while oral IFX solution had no efficacy. These results suggest that a pH-responsive FA-AC-based nanocomposite system can be a new platform for the site-selective oral delivery of therapeutic antibodies.

Abstract 1734: Encapsulating therapeutic antibodies for tumor specific activation and delivery using a clinically validated pH-sensitive nanoparticle platform

Abstract Background: Though antibodies for cancer treatment have achieved clinical and commercial success over the past few decades, a large portion are limited by suboptimal efficacy and on-target off-tumor toxicity due to ubiquitous expression of their targets. A plethora of molecular engineering approaches have been introduced to restrict the activity of antibodies solely to tumor instead of healthy tissue with the goal of improving the therapeutic index, such as masking the binding sites of antibodies with inhibitory domains. However, sophisticated modification is usually required while the outcomes are often mediocre. Previously we developed an ultra-pH sensitive nanoparticle platform named ON-BOARD. The strength of this technology stems from its ability to preferentially release the payload specifically in the acidic tumor microenvironment while staying intact in normal tissue. The safety and feasibility of using such a platform have been demonstrated by successful delivery of fluorophore to tumors for imaging of multiple tumor types in Phase I and II clinical trials with Pegsitacianine (formerly “ONM-100”). Pegsitacianine has been shown to be generally well-tolerated with an infusion-related reaction as the most common adverse event in the clinical trials conducted to date. Based on the clinical results, we present the ON-BOARD platform herein as a potential universal and effective tool for tumor specific activation and delivery of therapeutic antibodies without the need for sophisticated antibody chemistry or engineering. Methods: Biosimilar monoclonal antibodies of atezolizumab, cetuximab, pembrolizumab, trastuzumab, and ipilimumab with the same variable region sequences as the original pharmaceutical drugs were used to demonstrate encapsulation by the ON-BOARD platform and pH-dependent activation. Encapsulated antibodies were purified using SEC and the encapsulation efficiencies were quantified by HPLC. Particle size and uniformity were studied by DLS. The formulations were accessed for bioactivity in vitro under neutral pH or acidified conditions using appropriate cell-based reporter assays. Results: ON-BOARD nanoparticles successfully encapsulated the antibodies mentioned above without additional modification of the original antibody. Encapsulation efficiency ranged from 50-100%. The formulations were characterized as uniformly distributed particles < 100nm in size with good stability. In vitro assessment by cell-based reporter assays demonstrated > 100-fold activation window between the acid-activated and intact formulations. The pH-dependent activation was further confirmed by affinity and binding assay. Conclusions: The ON-BOARD pH-sensitive nanoparticle platform demonstrated potential as an effective and universal tool for tumor specific activation and delivery of antibody-based therapeutics. Citation Format: Gaurav Bharadwaj, Qingtai Su, Stephen Gutowski, Curran Parpia, Ashley Campbell, Jason Miller, Tian Zhao. Encapsulating therapeutic antibodies for tumor specific activation and delivery using a clinically validated pH-sensitive nanoparticle platform [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 1734.

Potentialities and Challenges of mRNA Vaccine in Cancer Immunotherapy.

Immunotherapy has become the breakthrough strategies for treatment of cancer in recent years. The application of messenger RNA in cancer immunotherapy is gaining tremendous popularity as mRNA can function as an effective vector for the delivery of therapeutic antibodies on immune targets. The high efficacy, decreased toxicity, rapid manufacturing and safe administration of mRNA vaccines have great advantages over conventional vaccines. The unprecedent success of mRNA vaccines against infection has proved its effectiveness. However, the instability and inefficient delivery of mRNA has cast a shadow on the wide application of this approach. In the past decades, modifications on mRNA structure and delivery methods have been made to solve these questions. This review summarizes recent advancements of mRNA vaccines in cancer immunotherapy and the existing challenges for its clinical application, providing insights on the future optimization of mRNA vaccines for the successful treatment of cancer.

Micro-ecology restoration of colonic inflammation by in-Situ oral delivery of antibody-laden hydrogel microcapsules.

In-situ oral delivery of therapeutic antibodies, like monoclonal antibody, for chronic inflammation treatment is the most convenient approach compared with other administration routes. Moreover, the abundant links between the gut microbiota and colonic inflammation indicate that the synergistic or antagonistic effect of gut microbiota to colonic inflammation. However, the antibody activity would be significantly affected while transferring through the gastrointestinal tract due to hostile conditions. Moreover, these antibodies have short serum half-lives, thus, require to be frequently administered with high doses to be effective, leading to low patient tolerance. Here, we develop a strategy utilizing thin shell hydrogel microcapsule fabricated by microfluidic technique as the oral delivering carrier. By encapsulating antibodies in these microcapsules, antibodies survive in the hostile gastrointestinal environment and rapidly release into the small intestine through oral administration route, achieving the same therapeutic effect as the intravenous injection evaluated by a colonic inflammation disease model. Moreover, the abundance of some intestinal microorganisms as the indication of the improvement of inflammation has remarkably altered after in-situ antibody-laden microcapsules delivery, implying the restoration of micro-ecology of the intestine. These findings prove our microcapsules are exploited as an efficient oral delivery agent for antibodies with programmable function in clinical application.

ADGRL4/ELTD1 Expression in Breast Cancer Cells Induces Vascular Normalization and Immune Suppression.

ELTD1/ADGRL4 expression is increased in the vasculature of a number of tumor types and this correlates with a good prognosis. Expression has also been reported in some tumor cells with high expression correlating with a good prognosis in hepatocellular carcinoma (HCC) and a poor prognosis in glioblastoma. Here we show that 35% of primary human breast tumors stain positively for ELTD1, with 9% having high expression that correlates with improved relapse-free survival. Using immunocompetent, syngeneic mouse breast cancer models we found that tumors expressing recombinant murine Eltd1 grew faster than controls, with an enhanced ability to metastasize and promote systemic immune effects. The Eltd1-expressing tumors had larger and better perfused vessels and tumor-endothelial cell interaction led to the release of proangiogenic and immune-modulating factors. M2-like macrophages increased in the stroma along with expression of programmed death-ligand 1 (PD-L1) on tumor and immune cells, to create an immunosuppressive microenvironment that allowed Eltd1-regulated tumor growth in the presence of an NY-ESO-1-specific immune response. Eltd1-positive tumors also responded better to chemotherapy which could explain the relationship to a good prognosis observed in primary human cases. Thus, ELTD1 expression may enhance delivery of therapeutic antibodies to reverse the immunosuppression and increase response to chemotherapy and radiotherapy in this subset of tumors. ELTD1 may be useful as a selection marker for such therapies. IMPLICATIONS: ELTD1 expression in mouse breast tumors creates an immunosuppressive microenvironment and increases vessel size and perfusion. Its expression may enhance the delivery of therapies targeting the immune system.

Harnessing the power of antibodies to fight bone metastasis.

Antibody-based therapies have proved to be of great value in cancer treatment. Despite the clinical success of these biopharmaceuticals, reaching targets in the bone microenvironment has proved to be difficult due to the relatively low vascularization of bone tissue and the presence of physical barriers. Here, we have used an innovative bone-targeting (BonTarg) technology to generate a first-in-class bone-targeting antibody. Our strategy involves the use of pClick antibody conjugation technology to chemically couple the bone-targeting moiety bisphosphonate to therapeutic antibodies. Bisphosphonate modification of these antibodies results in the delivery of higher conjugate concentrations to the bone metastatic niche, relative to other tissues. In xenograft mice models, this strategy provides enhanced inhibition of bone metastases and multiorgan secondary metastases that arise from bone lesions. Specific delivery of therapeutic antibodies to the bone, therefore, represents a promising strategy for the treatment of bone metastatic cancers and other bone diseases.

Biomaterials-Based Delivery of Therapeutic Antibodies for Cancer Therapy.

Considerable breakthroughs in the treatment of malignant tumors using antibody drugs, especially immunomodulating monoclonal antibodies (mAbs), have been made in the past decade. Despite technological advancements in antibody design and manufacture, multiple challenges face antibody-mediated cancer therapy, such as instability in vivo, poor tumor penetration, limited response rate, and undesirable off-target cytotoxicity. In recent years, an increasing number of biomaterials-based delivery systems have been reported to enhance the antitumor efficacy of antibody drugs. This review summarizes the advances and breakthroughs in integrating biomaterials with therapeutic antibodies for enhanced cancer therapy. A brief introduction to the principal mechanism of antibody-based cancer therapy is first established, and then various antibody immobilization strategies are provided. Finally, the current state-of-the-art in biomaterials-based antibody delivery systems and their applications in cancer treatment are summarized, highlighting how the delivery systems augment the therapeutic efficacy of antibody drugs. The outlook and perspective on biomaterials-based delivery of antitumor antibodies are also discussed.

Improved therapeutic antibody delivery to xenograft tumors using cavitation nucleated by gas-entrapping nanoparticles.

Aims: Testing ultrasound-mediated cavitation for enhanced delivery of the therapeutic antibody cetuximab to tumors in a mouse model. Methods: Tumors with strong EGF receptor expression were grown bilaterally. Cetuximab was coadministered intravenously with cavitation nuclei, consisting of either the ultrasound contrast agent Sonovueor gas-stabilizing nanoscale SonoTranParticles. One of the two tumors was exposed to focused ultrasound. Passive acoustic mapping localized and monitored cavitation activity. Both tumors were then excised and cetuximab concentrationwasquantified. Results: Cavitation increased tumoral cetuximab concentration. When nucleated by Sonovue, a 2.1-fold increase (95% CI 1.3- to3.4-fold) was measured, whereas SonoTranParticles gave a 3.6-fold increase (95% CI 2.3- to5.8-fold). Conclusions: Ultrasound-mediated cavitation, especially when nucleated by nanoscale gas-entrapping particles, can noninvasively increase site-specific delivery of therapeutic antibodies to solid tumors.

Phenylboronic-acid-based nanocomplex as a feasible delivery platform of immune checkpoint inhibitor for potent cancer immunotherapy

Inspired by our previous study, we report a simple yet effective platform for therapeutic antibody delivery. A polymeric phenylboronic acid (pPBA)–antibody nanocomplex was simply formulated by mixing pPBA and antibody, derived by the formation of a pH-responsive phenylboronic ester between the PBA group on pPBA and diol on the inherent glycosylation site of the antibody. We focused on the basic prerequisites for a successful delivery, protection from degradation during the circulation, and release at the target lesion. To evaluate the antibody delivery system, anti-PD-L1, one of the most common antibody therapeutics in immuno-oncology, and mouse colon cancer model with an MC-38 cell line were used. Several in-vitro assays reveal the outstanding protective effect of the nanocomplexes as well as the pH-responsive release of antibodies. Moreover, the anti-PD-L1 nanocomplex exhibited an enhanced circulation as well as a better accumulation in tumor lesions after administration in vivo, which led to a significant antitumor effect in comparison to that of a free antibody. Our nanocomplex platform is a promising antibody delivery system for application in conventional antibody-mediated therapies.