A CD25×TIGIT bispecific antibody induces anti-tumor activity through selective intratumoral Treg cell depletion.

Intratumoral regulatory T cells (Tregs) express high levels of CD25 and TIGIT, which are also recognized as markers of effector T cell (Teff) activation. Targeting these molecules each alone with monoclonal antibodies (mAbs) poses a risk of concurrently depleting both Teffs and peripheral Tregs, thereby compromising the effectiveness and selectivity of intratumoral Treg depletion. Here, leveraging the increased abundance of CD25+ TIGIT+ double-positive Tregs in the solid tumor microenvironment (but not in peripheral tissues), we explore the feasibility of using a CD25×TIGIT bispecific antibody (bsAb) to selectively deplete intratumoral Tregs. We initially constructed a bsAb co-targeting mouse CD25 and TIGIT, NSWm7210, and found that NSWm7210 conferred enhanced intratumoral Treg depletion, Teff activation, and tumor suppression as compared to the parental monotherapies in mouse models. We subsequently constructed a bsAb co-targeting human CD25 and TIGIT (NSWh7216), which preferentially eliminated CD25+ TIGIT+ double-positive cells over single-positive cells in vitro. NSWh7216 exhibited enhanced anti-tumor activity without toxicity of peripheral Tregs in CD25 humanized mice compared to the parental monotherapies. Our study illustrates the use of CD25×TIGIT bsAbs as effective agents against solid tumors based on selective depletion of intratumoral Tregs.

Electron Transporting Polymeric Materials with Partial Quaternization for High-Performance Organic Solar Cells.

Efficient cathode interfacial layers (CILs) have become a crucial component of organic solar cells (OSCs). Charge extraction barriers, interfacial trap states, and significant transport resistance may be induced due to the unfavorable cathode interlayer, limiting the device performance. In this study, poly(4-vinylpyridine) is used as the CIL for OSCs, and a new type of CIL named P4VP-I is synthesized through the quaternization strategy. Compared to P4VP, P4VP-I CIL exhibits enhanced conductivity and optimized work function. OSCs employing the P4VP-I ETL demonstrate prolonged carrier lifetime, suppressed charge recombination, and achieve higher power conversion efficiencies (PCE) than the commonly used ETLs such as PFN-Br and Phen-NaDPO.

Targeting TNFRSF25 by agonistic antibodies and multimeric TL1A proteins co-stimulated CD8+ T cells and inhibited tumor growth.

BACKGROUND: Tumor necrosis factor receptor superfamily 25 (TNFRSF25) is a T-cell co-stimulatory receptor. Expression of its ligand, TNF-like cytokine 1A (TL1A), on mouse tumor cells has been shown to promote tumor regression. This study aimed to develop TNFRSF25 agonists (both antibodies (Abs) and TL1A proteins) and to investigate their potential antitumor effects. METHODS: Anti-mouse TNFRSF25 (mTNFRSF25) Abs and multimeric TL1A proteins were generated as TNFRSF25 agonists. Their agonism was assessed in luciferase reporter and T-cell co-stimulation assays, and their antitumor effects were evaluated in syngeneic mouse tumor models. TNFRSF25 expression within the tumor microenvironment and the effects of an anti-mTNFRSF25 agonistic Ab on tumor-infiltrating T cells were evaluated by flow cytometry. Cell depletion assays were used to identify the immune cell types that contribute to the antitumor effect of the anti-mTNFRSF25 Ab. The Fc gamma receptor (FcγR) dependence of TNFRSF25 agonists was assessed in an in vivo T-cell expansion model and a mouse tumor model using Fc variants and FcγR-deficient mice. RESULTS: TNFRSF25 agonists exhibited antitumor effects in syngeneic mouse tumor models without causing observed side effects. We identified an anti-mTNFRSF25 agonistic Ab, 1A6-m1, which exhibited greater antitumor activity than a higher affinity anti-TNFRSF25 Ab which engages an overlapping epitope with 1A6-m1. 1A6-m1 activated CD8+ T cells and antigen-specific T cells, leading to tumor regression; it also induced long-term antitumor immune memory. Although activating TNFRSF25 by 1A6-m1 expanded splenic regulatory T (Treg) cells, it did not influence intratumoral Treg cells. Moreover, 1A6-m1's antitumor effects required the engagement of both inhibitory FcγRIIB and activating FcγRIII. Replacing 1A6-m1's CH1-hinge region with that of human IgG2 (h2) conferred enhanced antitumor effects. Finally, we also generated multimeric human and mouse TL1A fusion proteins as TNFRSF25 agonists, and they co-stimulated CD8+ T cells and reduced tumor growth, even in the absence of Fc-FcγR interactions. CONCLUSION: Our data demonstrates the potential of activating TNFRSF25 by Abs and multimeric TL1A proteins for cancer immunotherapy and provides insights into their development astherapeutics.

The anti-correlation effect of alkyl chain size on the photovoltaic performance of centrally extended non-fullerene acceptors.

Contrary to previous results, a unique anti-correlation effect of the alkyl chain size on the photovoltaic performance of acceptors was observed. For a centrally-extended acceptor, replacing linear alkyl chains (n-undecyl for CH-BBQ) on the thienothiophene unit with branched ones (2-butyloctyl for CH-BO) leads to a plunge in the power conversion efficiency of organic solar cells (18.12% vs. 11.34% for binary devices), while the largely shortened ones (n-heptyl for CH-HP) bring a surge in performance (18.74%/19.44% for binary/ternary devices). Compared with CH-BO, the more compact intermolecular packing of CH-HP facilitates carrier transport. The characterization of organic field effect transistors and carrier dynamics also echoes the above results. Molecular dynamics simulations indicate that the encounter of the branched alkyl chains and the extended central core hinders the effective interfacial interaction of polymer donors and acceptors, thus deteriorating the device performance. This work suggests that the conventional strategy for alkyl chain engineering of Y-series acceptors might need to be reconsidered in other molecular systems.

Fully Fused Indacenodithiophene-Centered Small-Molecule n-Type Semiconductors for High-Performance Organic Electronics.

Developing novel n-type organic semiconductors is an on-going research endeavour, given their pivotal roles in organic electronics and their relative scarcity compared to p-type counterparts. In this study, a new strategy was employed to synthesize n-type organic semiconductors featuring a fully fused conjugated backbone. By attaching two sets of adjacent amino and formyl groups to the indacenodithiophene-based central cores and triggering a tandem reaction sequence of a Knoevenagel condensation-intramolecular cyclization, DFA1 and DFA2 were realized. The solution-processed organic field effect transistors based on DFA1 exhibited unipolar n-type transport character with a decent electron mobility of ca. 0.10 cm2 V-1 s-1 (ca. 0.038 cm2 V-1 s-1 for DFA2 based devices). When employing DFA1 as a third component in organic solar cells, a high power conversion efficiency of 19.2 % can be achieved in ternary devices fabricated with PM6 : L8-BO : DFA1. This work provides a new pathway in the molecular engineering of n-type organic semiconductors, propelling relevant research forward.

Self-Adaptive Photodynamic-to-Photothermal Switch for Smart Antitumor Photoimmunotherapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) possess different merits in cancer phototherapy, but the tumor microenvironment becomes unfavorable during the phototheranostic progress. Herein, we report a self-adaptive cyanine derivative Cy5-TPA with the PDT-dominated state to PTT-dominated state autoswitch feature for enhanced photoimmunotherapy. The incorporation of rotatable triphenylamine (TPA) moiety renders Cy5-TPA with the temperature or intramolecular-motion regulated photoactivities, which shows preferable reactive oxygen species (ROS) generation at lower temperature while stronger photothermal conversion at higher ones. Such a promising feature permits the in situ switch from PDT-dominated state to PTT-dominated state along with intratumoral temperature increase during laser irradiation, which also works in line with the concurrently reduced intratumoral oxygen level, exhibiting a self-adaptive phototherapeutic behavior to maximize the phototherapeutic antitumor outcome. Most importantly, the self-adaptive PDT-dominated state to PTT-dominated state switch also facilitates the sequential generation and release of damage-associated molecular patterns during immunogenic cell death (ICD). Hence, Cy5-TPA demonstrates excellent photoimmunotherapy performance in ICD induction, dendritic cell maturation, and T cell activation for tumor eradication and metastasis inhibition.

Quantum dot-based light conversion strategy for customized cultivation of microalgae.

Microalgae are photosynthetic microorganisms with the potential to mitigate the atmospheric greenhouse effect by carbon fixation. However, their growth is typically limited by light availability. A wavelength converter utilizing red, blue, and green quantum dots (QDs) was developed to optimize light quality for enhancing microalgal production. The growth, lipid content, and eicosapentaenoic acid titer of Nannochloropsis increased by 11.2%, 9.5%, and 15.5% with red QDs, respectively. The biomass and triacylglycerol content of Phaeodactylum tricornutum increased by 8.6% and 35.0%, respectively. Simultaneously, biodiesel production was accelerated in Nannochloropsis (20.2%) and P. tricornutum (11.6%), and improved with increased cetane number and reduced iodine value. Furthermore, red QDs increased the growth and biomass accumulation of Nannochloropsis under low light, while green QDs shielded Nannochloropsis from photoinhibition under high light. This customizable QD-based methodology overcomes microalgal light limitations, demonstrating a universally applicable approach to improve microalgal cultivation and biochemical component production.

Binary All-polymer Solar Cells with a Perhalogenated-Thiophene-Based Solid Additive Surpass 18 % Efficiency.

Morphological control of all-polymer blends is quintessential yet challenging in fabricating high-performance organic solar cells. Recently, solid additives (SAs) have been approved to be capable in tuning the morphology of polymer: small-molecule blends improving the performance and stability of devices. Herein, three perhalogenated thiophenes, which are 3,4-dibromo-2,5-diiodothiophene (SA-T1), 2,5-dibromo-3,4-diiodothiophene (SA-T2), and 2,3-dibromo-4,5-diiodothiophene (SA-T3), were adopted as SAs to optimize the performance of all-polymer organic solar cells (APSCs). For the blend of PM6 and PY-IT, benefitting from the intermolecular interactions between perhalogenated thiophenes and polymers, the molecular packing properties could be finely regulated after introducing these SAs. In situ UV/Vis measurement revealed that these SAs could assist morphological character evolution in the all-polymer blend, leading to their optimal morphologies. Compared to the as-cast device of PM6 : PY-IT, all SA-treated binary devices displayed enhanced power conversion efficiencies of 17.4-18.3 % with obviously elevated short-circuit current densities and fill factors. To our knowledge, the PCE of 18.3 % for SA-T1-treated binary ranks the highest among all binary APSCs to date. Meanwhile, the universality of SA-T1 in other all-polymer blends is demonstrated with unanimously improved device performance. This work provide a new pathway in realizing high-performance APSCs.

Dielectric and Wavefunction Engineering of Electron Spin Lifetime in Colloidal Nanoplatelet Heterostructures.

Colloidal semiconductor nanoplatelets (NPLs) have emerged as low-cost and free-standing alternates of traditional quantum wells. The giant heavy- and light-hole splitting in NPLs allows for efficient optical spin injection. However, the electron spin lifetimes for prototypical CdSe NPLs are within a few picoseconds, likely limited by strong electron-hole exchange in these quantum- and dielectric-confined materials. Here how this hurdle can be overcome with engineered NPL-heterostructures is demonstrated. By constructing type-I CdSe/ZnS core/shell NPLs, dielectric screening inside the core is strongly enhanced, prolonging the electron spin polarization time (τesp) to over 30 ps (or 60 ps electron spin-flip time). Alternatively, by growing type-II CdSe/CdTe core/crown NPLs to spatially separate electron and hole wavefunctions, the electron-hole exchange is strongly suppressed, resulting in τesp as long as 300 ps at room temperature. This study not only exemplifies how the well-established synthetic chemistry of colloidal heterostructures can aid in spin dynamics control but also establishes the feasibility of room-temperature coherent spin manipulation in colloidal NPLs.

Engineering Carrier Dynamics in Halide Perovskites by Dynamical Lattice Distortion.

The electronic structure of halide perovskites is central to their carrier dynamics, enabling the excellent optoelectronic performance. However, the experimentally resolved transient absorption spectra exhibit large discrepancies from the commonly computed electronic structure by density functional theory. Using pseudocubic CsPbI3 as a prototype example, here, it is unveiled with both ab initio molecular dynamics simulations and transmission electron microscopy that there exists pronounced dynamical lattice distortion in the form of disordered instantaneous octahedral tilting. Rigorous first-principles calculations reveal that the lattice distortion substantially alters the electronic band structure through renormalizing the band dispersions and the interband transition energies. Most notably, the electron and hole effective masses increase by 65% and 88%, respectively; the transition energy between the two highest valence bands decreases by about one half, agreeing remarkably well with supercontinuum transient-absorption measurements. This study further demonstrates how the resulting electronic structure modulates various aspects of the carrier dynamics such as carrier transport, hot-carrier relaxation, Auger recombination, and carrier multiplication in halide perovskites. The insights provide a pathway to engineer carrier transport and relaxation via lattice distortion, enabling the promise to achieve ultrahigh-efficiency photovoltaic devices.

Depression in maintenance hemodialysis patients: What do we need to know?

Chronic kidney disease (CKD) is now recognized as a major public health problem in the world. The global prevalence of CKD is estimated at 13.4% (11.7-15.1%), with an estimated 490.2 to 7.083 million patients with End stage renal disease requiring renal replacement therapy. Hemodialysis is the main treatment for End stage renal disease patients because of its high safety and efficiency. The survival time of these patients was significantly prolonged, but many psychological problems followed. Depression is a type of mood disorder caused by a variety of causes, often manifested as disproportionate depression and loss of interest, sometimes accompanied by anxiety, agitation, even hallucinations, delusions and other psychotic symptoms. Depression has become the most common mental disorder in maintenance hemodialysis (MHD) patients according to the meta-analysis. In recent years, depression has seriously affected the quality of life and prognosis of MHD patients from dietary, sleep, treatment adherence, energy and other dimensions. This article reviews the epidemiology, etiology, diagnosis and treatment of depression in MHD patients.

Electronic Configuration Tuning of Centrally Extended Non-Fullerene Acceptors Enabling Organic Solar Cells with Efficiency Approaching 19 .

In the molecular optimizations of non-fullerene acceptors (NFAs), extending the central core can tune the energy levels, reduce nonradiative energy loss, enhance the intramolecular (donor-acceptor and acceptor-acceptor) packing, facilitate the charge transport, and improve device performance. In this study, a new strategy was employed to synthesize acceptors featuring conjugation-extended electron-deficient cores. Among these, the acceptor CH-BBQ, embedded with benzobisthiadiazole, exhibited an optimal fibrillar network morphology, enhanced crystallinity, and improved charge generation/transport in blend films, leading to a power conversion efficiency of 18.94 % for CH-BBQ-based ternary organic solar cells (OSCs; 18.19 % for binary OSCs) owing to its delicate structure design and electronic configuration tuning. Both experimental and theoretical approaches were used to systematically investigate the influence of the central electron-deficient core on the properties of the acceptor and device performance. The electron-deficient core modulation paves a new pathway in the molecular engineering of NFAs, propelling relevant research forward.

A Cascade Strategy Boosting Hydroxyl Radical Generation with Aggregation-Induced Emission Photosensitizers-Albumin Complex for Photodynamic Therapy.

Effective photodynamic therapy (PDT) requires photosensitizers (PSs) to massively generate type I reactive oxygen species (ROS) in a less oxygen-dependent manner in the hypoxia tumor microenvironment. Herein, we present a cascade strategy to boost type I ROS, especially hydroxyl radical (OH·-), generation with an aggregation-induced emission (AIE) photosensitizer-albumin complex for hypoxia-tolerant PDT. The cationic AIE PS TPAQ-Py-PF6 (TPA = triphenylamine, Q = anthraquinone, Py = pyridine) contains three important moieties to cooperatively enhance free radical generation: the AIE-active TPA unit ensures the effective triplet exciton generation in aggregate, the anthraquinone moiety possesses the redox cycling ability to promote electron transfer, while the cationic methylpyridinium cation further increases intramolecular charge transfer and electron separation processes. Inserting the cationic TPAQ-Py-PF6 into the hydrophobic domain of bovine serum albumin nanoparticles (BSA NPs) could greatly immobilize its molecular geometry to further increase triplet exciton generation, while the electron-rich microenvironment of BSA ultimately leads to OH·- generation. Both experimental and theoretical results confirm the effectiveness of our molecular cationization and BSA immobilization cascade strategy for enhancing OH·- generation. In vitro and in vivo experiments validate the excellent antitumor PDT performance of BSA NPs, superior to the conventional polymeric encapsulation approach. Such a multidimensional cascade strategy for specially boosting OH·- generation shall hold great potential in hypoxia-tolerant PDT and related antitumor applications.

Clinical heterogeneity of NLRP12-associated autoinflammatory diseases.

Nod-like receptor family pyrin domain-containing protein 12 (NLRP12) is one of the critical pattern recognition receptors which participates in the regulation of multiple inflammatory responses. Mutations in NLRP12 cause exceptionally rare NLRP12-associated autoinflammatory disease (NLRP12-AID). So far, very few patients with NLRP12-AID have been identified worldwide; therefore, data on the clinical phenotype and genetic profile are limited. In this study, we reported 10 patients who presented mainly with periodic fever syndrome or arthritis. Next-generation sequencing (NGS) identified 6 heterozygous mutations of NLRP12, including 2 novel null mutations. Of the patients, some with same mutations showed different clinical features. Compared to healthy controls, the increased levels of cytokines were revealed in the patients' plasmas, as well as in the supernatants of patients' cells stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α). The missense mutations did not change the protein expression; but decreased level of NLRP12 protein was shown in the null mutations. And in vitro expression assay demonstrated a truncating protein induced by the frameshift mutation. Further functional studies revealed the deleterious effect of mutations on nuclear factor-kappa B (NF-κB) signaling. Both the null and missense mutations impaired their inhibition of NF-κB activation induced by p65. Collectively, this study reported a relatively large NLRP12-AID case series. Our findings expand the clinical spectrum, and reinforce the diversity of genetic mutations and clinical phenotypes. The NLRP12-associated disorder should be considered when autoinflammatory diseases are encountered in the clinical practice, especially for patients presenting with periodic fever but no other genetic cause identified.

A new perspective on Alzheimer's disease: m6A modification.

As a neurodegenerative disease, Alzheimer's disease (AD) is characterized by synaptic loss, extracellular plaques of amyloid accumulation, hyperphosphorylation of tau, and neuroinflammation. Various biological processes are affected by epitranscriptomic modifications, which regulate the metabolism of mRNA in cells and regulate the expression of genes. In response to changes in m6A modification levels, the nervous system becomes dysfunctional and plays a significant role in the development of Alzheimer's disease. As a result of recent research, this paper reviews advances in the understanding of the regulatory mechanisms of m6A modification in the occurrence and development of AD. In addition, the article discusses recent research techniques related to animal models of m6A and AD. Furthermore, it discusses the possibility of studying the pathogenesis of AD at the level of the epitranscriptome, identifying early diagnostic markers, and screening for effective treatment options.

Differential effects of petroleum-based and bio-based microplastics on anaerobic digestion: A review.

The number of plastics is increasing owing to the rapid development of the plastics industry. Microplastics (MPs) are formed during the use of both petroleum-based plastics and newly developed bio-based plastics. These MPs are inevitably released into the environment and are enriched in wastewater treatment plant sludge. Anaerobic digestion is a popular sludge stabilization method for wastewater treatment plants. Understanding the potential impacts of different MPs on anaerobic digestion is critical. This paper provides a comprehensive review of the mechanisms of petroleum-based MPs and bio-based MPs in anaerobic digestion methane production and compares their potential effects on biochemical pathways, key enzyme activities, and microbial communities. Finally, it identifies problems that must be solved in the future, proposes the focus of future research, and predicts the future development direction of the plastics industry.

Antibacterial Mechanism of Shikonin Against Vibrio vulnificus and Its Healing Potential on Infected Mice with Full-Thickness Excised Skin.

Shikonin has anticancer, anti-inflammatory, and wound healing activities. Vibrio vulnificus is an important marine foodborne pathogen with a high fatality rate and rapid pathogenesis that can infect humans through ingestion and wounds. In this study, the antibacterial activity and possible antibacterial mechanism of shikonin against V. vulnificus were investigated. In addition, the ability of shikonin to control V. vulnificus infection in both pathways was assessed by artificially contaminated oysters and full-thickness excised skin-infected mice. Shikonin treatment can cause abnormal cell membrane function, as evidenced by hyperpolarization of the cell membrane, significant decreased intracellular ATP concentration (p < 0.05), significant increased intracellular reactive oxygen species and malondialdehyde content (p < 0.05), decreased cell membrane integrity, and changes in cell morphology. Shikonin at 40 and 80 µg/mL reduced bacterial numbers in shikonin-contaminated oysters by 3.58 and 2.18 log colony-forming unit (CFU)/mL. Shikonin can promote wound healing in mice infected with V. vulnificus by promoting the formation of granulation tissue, hair follicles, and sebaceous glands, promoting epithelial cell regeneration and epidermal growth factor production. These findings suggest that shikonin has a strong inactivation effect on V. vulnificus and can be used in food production and wound healing to effectively control V. vulnificus and reduce the number of diseases associated with it.

Inhibition of castration-resistant prostate cancer growth by genistein through suppression of AKR1C3.

Background: Prostate cancer is the second leading cause of cancer-related death among males in America. The patients' survival time is significantly reduced after prostate cancer develops into castration-resistant prostate cancer (CRPC). It has been reported that AKR1C3 is involved in this progression, and that its abnormal expression is directly correlated with the degree of CRPC malignancy. Genistein is one of the active components of soy isoflavones, and many studies have suggested that it has a better inhibitory effect on CRPC. Objective: This study aimed to investigate the antitumor effect of genistein on CRPC and the potential mechanism of action. Design: A xenograft tumor mouse model established with 22RV1 cells was divided into the experimental group and the control group, and the former was given 100 mg/kg.bw/day of genistein, with 22RV1, VCaP, and RWPE-1 cells cultured in a hormone-free serum environment and treated with different concentrations of genistein (0, 12.5, 25, 50, and 100 µmol/L) for 48 h. Molecular docking was used to elucidate the molecular interactions between genistein and AKR1C3. Results: Genistein inhibits CRPC cell proliferation and in vivo tumorigenesis. The western blot analysis confirmed that the genistein significantly inhibited prostate-specific antigen production in a dose-dependent manner. In further results, AKR1C3 expression was decreased in both the xenograft tumor tissues and the CRPC cell lines following genistein gavage feeding compared to the control group, with the reduction becoming more obvious as the concentration of genistein was increased. When the genistein was combined with AKR1C3 small interfering ribonucleic acid and an AKR1C3 inhibitor (ASP-9521), the inhibitory effect on the AKR1C3 was more pronounced. In addition, the molecular docking results suggested that the genistein had a strong affinity with the AKR1C3, and that it could be a promising AKR1C3 inhibitor. Conclusion: Genistein inhibits the progression of CRPC via the suppression of AKR1C3.

A pH-dependent anti-CD47 antibody that selectively targets solid tumors and improves therapeutic efficacy and safety.

BACKGROUND: The antiphagocytic molecule CD47 is overexpressed in a wide variety of cancer cells, and antibodies targeting CD47 for cancer therapies are currently under intensive investigation. However, owing to the ubiquitous expression of CD47 on healthy cells, anti-CD47 therapies often achieve only weak therapeutic benefits and can induce severe side effects. Here, we report the generation of a pH-dependent anti-CD47 antibody (BC31M4) which selectively binds to tumors under the acidic solid tumor microenvironment. METHODS: BC31M4 was generated using antibody phage display and a pH-dependent selection strategy. The pH-dependent binding and blocking activities of BC31M4 were verified using in vitro assays, and the structural basis of the pH-dependent binding property was characterized. BC31M4's antitumor effect was confirmed by both phagocytosis assays and studies in xenograft models. The tumor selectivity, mechanism of action, PK properties, side effects, and therapeutic efficacy were further evaluated in humanized (hCD47 and its receptor hSIRPα) immunocompetent syngeneic mouse models. RESULTS: The crystal structure reveals that two histidines locate within the CDRs of the light chain directly contribute to the pH-dependent binding of BC31M4. BC31M4 promotes macrophage phagocytosis of tumor cells more potently at acidic-pH than at physiological-pH. Our hCD47/hSIRPα humanized syngeneic mouse model results demonstrated that BC31M4 selectively accumulates in tumors but not in normal tissues. BC31M4 causes minimal side effects and exhibits superior PK properties as compared to the other examined anti-CD47 antibodies. When combined with adoptive T cell transfer, BC31M4 efficiently promotes adaptive immune responses against tumors and also induces immune memory. Moreover, we show that BC31M4's antitumor effects rely on an Fc that mediates strong effector functions. CONCLUSIONS: Our study illustrates that the development of a tumor-selective, pH-dependent anti-CD47 antibody safely confers strong therapeutic effects against solid tumors, thus providing a promising therapeutic strategy to overcome the challenges of anti-CD47 therapy.

An anti-CD98 antibody displaying pH-dependent Fc-mediated tumour-specific activity against multiple cancers in CD98-humanized mice.

The cell-surface glycoprotein CD98-a subunit of the LAT1/CD98 amino acid transporter-is an attractive target for cancer immunotherapies, but its widespread expression has hampered the development of CD98-targeting antibody therapeutics. Here we report that an anti-CD98 antibody, identified via the screening of phage-display libraries of CD98 single-chain variable fragments with mutated complementarity-determining regions, preserves the physiological function of CD98 and elicits broad-spectrum crystallizable-fragment (Fc)-mediated anti-tumour activity (requiring Fcγ receptors for immunoglobulins, macrophages, dendritic cells and CD8+ T cells, as well as other components of the innate and adaptive immune systems) in multiple xenograft and syngeneic tumour models established in CD98-humanized mice. We also show that a variant of the anti-CD98 antibody with pH-dependent binding, generated by solving the structure of the antibody-CD98 complex, displayed enhanced tumour-specific activity and pharmacokinetics. pH-dependent antibody variants targeting widely expressed antigens may lead to superior therapeutic outcomes.