Cynomolgus Research Articles

An accelerated Parkinson’s disease monkey model using AAV-α-synuclein plus poly(ADP-ribose)

The etiology of Parkinson's disease (PD) remains elusive, and the limited availability of suitable animal models hampers research on pathogenesis and drug development. We report the development of a cynomolgus monkey model of PD that combines adeno-associated virus (AAV)-mediated overexpression of α-synuclein into the substantia nigra with an injection of poly(ADP-ribose) (PAR) into the striatum. Our results show that pathological processes were accelerated, including dopaminergic neuron degeneration, Lewy body aggregation, and hallmarks of inflammation in microglia and astrocytes. Behavioral phenotypes, dopamine transporter imaging, and transcriptomic profiling further demonstrate consistencies between the model and patients with PD. This model can help to determine the mechanisms underlying PD impacted by α-synuclein and PAR and aid in the accelerated development of therapeutic strategies for PD.

Mucus-inspired lubricative antibacterial coating to reduce airway complications in an intubation cynomolgus monkey model

Endotracheal intubation-related complications are common in clinical, and there are currently no effective strategies to address these matters. Inspired by the biological characteristics of human airway mucus (HAM), an artificial airway mucus (ARM) coating is straightforwardly constructed by combining carboxymethyl chitosan with methyl cellulose. The ARM coating exhibited excellent lubricity (coefficient of friction (CoF) = 0.05) and hydrophilicity (water contact angle (WCA) = 21.3°), and was capable of coating both the internal and external surfaces of the endotracheal tube (ETT). In vitro experiments demonstrated that the ARM coating not only showed good broad-spectrum antibacterial activity, but also significantly reduced nonspecific protein adhesion. Through an in vivo intubation cynomolgus monkey model, ARM-coated ETT potently mitigated airway injury and inflammation, and was highly potential to prevent bacterial infection and catheter blockage. This work offers a promising avenue for the development of airway-friendly invasive devices.

Graft survival of major histocompatibility complex deficient stem cell-derived retinal cells

BackgroundGene editing of immunomodulating molecules is a potential transplantation strategy to control immune rejection. As we noticed the successful transplantation of retinal pigment epithelium (RPE) derived from embryonic stem cells of a cynomolgus monkey that accidentally lacked MHC class II (MHC-II) molecules, we hypothesized immune rejection could be evaded by suppressing MHC-II.MethodsGene editing by the Crispr/Cas9 system was performed in induced pluripotent stem cells derived from a cynomolgus monkey (miPSCs) for targeted deletion of the gene coding class II MHC trans-activator (CIITA). Then the CIITA-knocked out miPSCs were differentiated into RPE cells to generate miPSC-derived MHC-II knockout RPE. The MHC-II knockout or wild-type RPEs were transplanted into the eyes of healthy cynomolgus monkeys. All monkeys used in this study were male.ResultsHere we show when MHC-II knockout RPE are transplanted into monkey eyes, they show suppressed immunogenicity with no infiltration of inflammatory cells, leading to successful engraftment.ConclusionsOur results reasonably evidence the efficacy of MHC-II knockout iPSC-RPE transplants for clinical application.

Brief Report on The Population Survey Long-tailed Macaque (Macaca fascicularis [Raffles,1821]) in West Nusa Tenggara, Indonesia

Survey on the population and distribution of long-tailed macaque (Macaca fascicularis [Raffles, 1821]) in the administrative areas of West Nusa Tenggara Province have been conducted during June-July 2024 to examine the distribution and population status on the macaque. The on-road reconnaissance survey, interview and literature studies have applied to collect data. We recorded 6146 individuals from 307 groups of long-tailed macaques in eight regencies. Of the 6146 individuals of long-tailed macaques, 1532 individuals are recorded living in conservation area, while 4614 individuals live in outside conservation area, respectively. The number of individuals and troops of the monkey showed us the minimum number that can be recorded. Further study needs to be conducted in addressed to dig more information on the existence of long-tailed macaque in West Nusa Tenggara. Furthermore, population information and distribution of long-tailed macaques could be the basic knowledge on the population management efforts in the future.

Diversity and abundance of mammals and aves in the Gunung Leuser National Park area, Bukit Lawang, Bahorok District, Langkat Regency, North Sumatra

Gunung Leuser National Park, located in Bukit Lawang, Langkat Regency, is renowned for its rich biodiversity, hosting a significant number of bird and mammal species. This study aimed to assess the diversity and abundance of mammals and birds in the park. Conducted from May 23 to 25, 2024, using Visual Encounter Surveys (VES) along a 1,000-meter transect, the research identified 8 mammal species with a total of 84 individuals, including Presbytis thomasi and Macaca fascicularis as the most prevalent. Additionally, 12 bird species with 87 individuals were recorded, dominated by the Hirundinidae family, notably Hirundo rustica and Hirundo tahitica. Diversity indices indicated moderate species diversity for both mammals (H' = 1.58) and birds (H' = 2.02), with high evenness (E = 0.78) in both groups, suggesting stable communities. The results highlight the park's significant biodiversity and the need for repeated surveys to refine data accuracy and enhance conservation efforts.

Recovery of independent ambulation after complete spinal cord transection in the presence of the neuroprotectant polyethylene glycol in monkeys

ObjectiveDespite the conventional belief that motor function and sensation distal to the site of a complete spinal cord transection are irretrievable, our research has demonstrated significant motor recovery in mice, rats, and dogs by applying polyethylene glycol (PEG) topically via a syringe directly to the contact interface of transected spinal cord. However, before implementing this technology in human subjects, validating PEG's efficacy and enduring impact through experimentation on non-human primates is imperative. MethodsTwo 4-year-old female Macaca fascicularis monkeys underwent complete dorsal cord transection at T10. Postoperative behavioral assessment, electrophysiologic monitoring, and neuroimaging examinations were recorded, and tissues were obtained for histological examination at the end of study. ResultsThe monkey whose spinal cord had been fully transected in the presence of PEG developed useful recovery already at 3 months and near-complete recovery of motor function in the hind-limbs at 18 months. The control animal without PEG remained paralyzed. Cortical somatosensory evoked potentials recovered postoperatively only in PEG-treated monkey vs none in the control. Diffusion tensor imaging showed re-establishment of continuity of the white matter in PEG-treated monkey, but not in the control. Moreover, histology revealed intact neuronal bodies, axons, and myelin tissue at the spinal cord transection site in PEG-treated monkey only. ConclusionThis report suggests that in primates, an acutely transected spinal cord can be re-fused in the presence of PEG with restoration of neural continuity and functional recovery of motor activity distal to the site of transection.

MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients.

Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides. We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ42, the pathogenic self-aggregating species of Aβ. MEDI1814 reduces free Aβ42 without impacting Aβ40 in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration. MEDI1814 administration to patients with Alzheimer's disease (AD; n=57) in single or repeat doses up to 1800mg intravenously or 200mg subcutaneously was associated with a favorable safety and tolerability profile. No cases of amyloid-related imaging abnormalities were observed. Predictable dose-proportional changes in serum exposures for MEDI1814 were observed across cohorts. Cerebrospinal fluid (CSF) analysis demonstrated central nervous system penetration of MEDI1814. Pharmacodynamic data showed dose-dependent suppression of free Aβ42, increases in total (bound and free) Aβ42, but no change in total Aβ40 in CSF across doses. MEDI1814 offers a differentiated approach to impacting Aβ in AD via selective reduction of free Aβ42.

Characterizing the rhythmic oscillations of gut bacterial and fungal communities and their rhythmic interactions in male cynomolgus monkeys.

The rhythmic oscillation of gut microbiota can impact the physiology activity and disease susceptibility of the host. Until now, most of the studies are focused on bacterial microbes, ignoring other components of gut microbes, such as fungal microbes (mycobiota). Besides, only few studies have addressed the rhythmic correlations between gut bacteria and fungi. Here, we analyzed the rhythmic oscillations of bacterial and fungal communities in male cynomolgus monkeys by performing 16S rRNA and ITS amplicon sequencing. Apart from identifying the rhythmically oscillated bacterial and fungal microbes, we conducted the correlation analysis between these two microbial communities and found that the intestinal bacteria and fungi exhibited close interactions rhythmically, with the most interactions occurring at ZT12. Thus, our study not only investigated the rhythmic oscillations of gut bacterial and fungal communities in male cynomolgus monkeys but also uncovered their rhythmic interactions.

Sleep dysfunction and gut dysbiosis related amino acids metabolism disorders in cynomolgus monkeys after middle cerebral artery occlusion

IntroductionThis study aimed to explore the characteristics of post-stroke sleep dysfunction and verify their association with gut dysbiosis and the related amino acid metabolism disorders. This was achieved by using fecal microbiota transplantation (FMT) in a non-human primate stroke model. MethodsTwenty adult male cynomolgus monkeys were divided into the sham (n = 4), middle cerebral artery occlusion (MCAO, n = 5), MCAO + FMT (n = 3), and donor (n = 8) groups. The MCAO+FMT group received FMT at post-MCAO week 4. Sleep parameters, gut microbiota, gamma-aminobutyric acid (GABA), and glutamine (Gln) in the cerebrospinal fluid (CSF) were measured at baseline and postoperative weeks 4, 8, and 12. ResultsAt postoperative weeks 4, 8, and 12, the MCAO group showed decreased sleep efficiency, measured as the percentage of sleep during the whole night (82.3 ± 3.2 % vs 91.3 ± 2.5 %, 79.0 ± 3.75 % vs 90.8 ± 3.2 %, and 69.5 ± 4.8 % vs 90.5 ± 2.7 %; all P < 0.05), lower relative abundance of Lactobacillus (all P < 0.05), and reduced GABA concentrations in the CSF (317.3 ± 30.6 nmol/L vs 437.7 ± 25.6 nmol/L, 303.1 ± 48.9 nmol/L vs 4 40.9 ± 37.8 nmol/L, and 337.9 ± 49.4 nmol/L vs 457.4 ± 39.2 nmol/L; all P < 0.05) compared with the sham group. Sleep efficiency at post-FMT weeks 4 and 8 (84.7 ± 1.1 % vs 79.0 ± 3.75 %, and 84.1 ± 2.0 % vs 69.5 ± 4.8 %; both P < 0.05) and GABA concentration in the CSF at post-FMT week 4 (403.1 ± 25.4 nmol/L vs 303.1 ± 48.9 nmol/L, P < 0.05) was higher in the MCAO+FMT group than in the MCAO group. ConclusionsPost-stroke sleep dysfunction in monkeys is characterized by impaired sleep coherence, associated with decreased levels of probiotics such as Lactobacillus, GABA, and Gln in the CSF and can be ameliorated using FMT.

Evaluating the Effect of a Probiotic on Prevention of Diarrhea, Stress Response, and Social Interactions in a Colony of Macaca fascicularis

Background: Social housing changes are associated with diarrhea in macaques, presumably due to stress. Objective: Since probiotics are utilized in humans for diarrhea, we tested the effectiveness of a species- specific probiotic, SDPro™ (composition: ~2 billion CFU each of live Lactobacillus reuteri and Saccharomyces boulardii), to prevent relocation-associated diarrhea. Assessments of the gutmicrobiome and diarrhea severity were made. Behavioral observations and cortisol levels were examined after relocation to test the effects of the probiotic treatment. Methods: The probiotic was administered to 60 juvenile macaques of both sexes (Probiotic +) and outcomes were compared to 60 control (Probiotic -) macaques. The effects on gut microbiome composition were analyzed via 16s microbiome analysis in half the animals from both groups. Social behaviors were monitored twice-weekly in the morning and afternoon for five weeks following 10- days of SDPro™ administration in 56 subjects and hair cortisol was assayed. Results: Probiotic administration altered beta, but not alpha, diversity, and caused changes in taxa abundance at the phylum, genus, and species levels. The Probiotic + group was enriched in Firmicutes, Clostridium, and Lactobacillus and diminished in Bacteriodies (p’s &lt; 0.05) compared to controls. Although SDPro™ did not alter diarrhea incidence following relocation, it reduced diarrhea severity in males only. Males also exhibited higher cortisol levels than females but there was no probiotic effect. Probiotic treatment had minor behavioral effects; the typical reduction in locomotion seen in the afternoon was eliminated. Conclusion: The results suggest that SDPro™ may be a viable tool to prevent relocation-induced diarrhea in juvenile male macaques.

Intravenous Bacillus Calmette-Guérin (BCG) Induces a More Potent Airway and Lung Immune Response than Intradermal BCG in Simian Immunodeficiency Virus-infected Macaques.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading causes of death due to an infectious agent. Coinfection with HIV exacerbates M. tuberculosis infection outcomes in people living with HIV. Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, is effective in infants, but its efficacy in adolescents and adults is limited. In this study, we investigated the immune responses elicited by BCG administered via i.v. or intradermal (i.d.) routes in SIV-infected Mauritian cynomolgus macaques (MCM) without the confounding effects of M. tuberculosis challenge. We assessed the impact of vaccination on T cell responses in the airway, blood, and tissues (lung, thoracic lymph nodes, and spleen), as well as the expression of cytokines, cytotoxic effectors, and key transcription factors. Our results showed that i.v. BCG induces a robust and sustained immune response, including tissue-resident memory T cells in lungs, polyfunctional CD4+ and CD8αβ+ T cells expressing multiple cytokines, and CD8αβ+ T cells and NK cells expressing cytotoxic effectors in airways. We also detected higher levels of mycobacteria-specific IgG and IgM in the airways of i.v. BCG-vaccinated MCM. Although i.v. BCG vaccination resulted in an influx of tissue-resident memory T cells in lungs of MCM with controlled SIV replication, MCM with high plasma SIV RNA (>105 copies/ml) typically displayed reduced T cell responses, suggesting that uncontrolled SIV or HIV replication would have a detrimental effect on i.v. BCG-induced protection against M. tuberculosis.

A cynomolgus monkey E. coli urinary tract infection model confirms efficacy of new FimH vaccine candidates.

The increase in urinary tract infections (UTI) caused by antibiotic-resistant Escherichia coli requires the development of new therapeutic agents and prophylactic vaccines. To evaluate the efficacy of new lead candidates, we implemented a cynomolgus macaque UTI challenge model that mimics human uncomplicated cystitis in response to transurethral challenge with a multidrug-resistant (MDR) E. coli serotype O25b ST131 isolate. E. coli fimbrial adhesin FimH and O-antigens are separately under clinical evaluation by others as vaccine candidates to prevent UTI and invasive urosepsis disease, respectively. Accordingly, we assessed the protective efficacy of three 50-µg intramuscular doses of a novel recombinant FimH antigen adjuvanted with liposomal QS21/MPLA compared with saline placebo in groups of nine animals. A third group was vaccinated with this FimH formulation in combination with 1 µg each of a four-valent mixture of serotype O1a, O2, O6, and O25b O-antigen CRM197 lattice glycoconjugates. Both vaccines elicited high levels of serum FimH IgG and adhesin blocking antibodies at the time of bacterial challenge and, for the combination group, O-antigen-specific antibodies. Following bacterial challenge, both vaccinated groups showed >200- and >700-fold reduction in bacteriuria at day 2 and day 7 post-infection compared with placebo, respectively. In parallel, both vaccines significantly reduced levels of inflammatory biomarkers IL-8 and myeloperoxidase in the urine at day 2 post-infection relative to placebo. Results provide preclinical proof-of-concept for the prevention of an MDR UTI infection by these new vaccine formulations.

Preclinical Evaluation of STI-8811, a Novel Antibody-Drug Conjugate Targeting BCMA for the Treatment of Multiple Myeloma.

Treatment for patients with multiple myeloma has experienced rapid development and improvement in recent years; however, patients continue to experience relapse, and multiple myeloma remains largely incurable. B-cell maturation antigen (BCMA) has been widely recognized as a promising target for treatment of multiple myeloma due to its exclusive expression in B-cell linage cells and its critical role in the growth and survival of malignant plasma cells. Here, we introduce STI-8811, a BCMA-targeting antibody-drug conjugate (ADC) linked to an auristatin-derived duostatin payload via an enzymatically cleavable peptide linker, using our proprietary C-lock technology. STI-8811 exhibits target-specific binding activity and rapid internalization, leading to G2/M cell-cycle arrest, caspase 3/7 activation, and apoptosis in BCMA-expressing tumor cells in vitro. Soluble BCMA (sBCMA) is shed by multiple myeloma cells into the blood and increases with disease progression, competing for ADC binding and reducing its efficacy. We report enhanced cytotoxic activity in the presence of high levels of sBCMA compared with a belantamab mafodotin biosimilar (J6M0-mcMMAF). STI-8811 demonstrated greater in vivo activity than J6M0-mcMMAF in solid and disseminated multiple myeloma models, including tumor models with low BCMA expression and/or in large solid tumors representing soft-tissue plasmacytomas. In cynomolgus monkeys, STI-8811 was well tolerated, with toxicities consistent with other BCMA-targeting ADCs with auristatin payloads in clinical studies. STI-8811 has the potential to outperform current clinical candidates with lower toxicity and higher activity under conditions found in patients with advanced disease. Significance: STI-8811 is a BCMA-targeting ADC carrying a potent auristatin derivative. We report unique binding properties which maintain potent cytotoxic activity under sBCMA-high conditions that hinder the clinical efficacy of current BCMA-targeting ADC candidates. Beyond disseminated models of multiple myeloma, we observed efficacy in solid tumor models of plasmacytomas with low and heterogenous BCMA expressions at a magnitude and duration of response exceeding that of clinical comparators.

A novel AAV9-dual microRNA-vector targeting GRIK2 in the hippocampus as a treatment for mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (mTLE) is the most prevalent type of epilepsy in adults. First and subsequent generations of anti-epileptic therapy regimens fail to decrease seizures in a large number of patients suffering from mTLE, leaving surgical ablation of part of the hippocampus as the only therapeutic option to potentially reach seizure freedom. GluK2 has recently been identified as a promising target for the treatment of mTLE using gene therapy. Here, we engineered an adeno-associated virus serotype 9 vector expressing a cluster of two synthetic microRNAs (miRNAs), expressed from the human synapsin promoter, that target GRIK2 mRNA. Intra-hippocampal delivery of this vector in a mouse model of mTLE significantly reduced GRIK2 expression and daily seizure frequency. This treatment also improved the animals' health, reduced their anxiety, and restored working memory. Focal administration of the vector to the hippocampus of cynomolgus monkeys in GLP toxicology studies led to the selective transduction of hippocampal neurons with little exposure elsewhere in the brain and no transduction outside the central nervous system. Expression of miRNAs in hippocampal neurons resulted in substantially decreased GRIK2 mRNA expression. These data suggest that the intra-hippocampal delivery of a GMP-grade AAV9 coding for a synthetic miRNAs targeting GRIK2 is a promising treatment strategy for mTLE.

Development of a novel humanized anti-TSLP monoclonal antibody, QX008N, and exploration of combination therapy of anti-TSLP antibody and anti-IL-4R antibody

BackgroundSevere asthma is a complex and chronic respiratory disease, and current conventional treatments are not effective in controlling the patients’ condition. Thymic stromal lymphopoietin (TSLP) is a key regulatory factor in the initiation and maintenance of asthma. Thus, blocking TSLP during allergic inflammation emerges as a promising therapeutic approach; however, novel anti-TSLP therapies remain to be developed. Furthermore, the importance of other signaling molecules, such as IL-4 and IL-13, should be considered. Moreover, to the best of our knowledge, the inhibitory effect of binding upstream and downstream signaling molecules has not been assessed. PurposeThis study aimed to develop a novel, humanized anti-TSLP antibody and explore the enhancement in its efficacy when combined with anti-IL-4R antibodies to treat asthma. ResultsQX008N, derived from a rabbit antibody platform, exhibits a high affinity for TSLP and superior efficacy in blocking TSLP-induced signaling pathways and inflammation in vitro compared with Tezepelumab. In a cynomolgus monkey asthma model, QX008N ameliorated lung function and reduced the levels of eosinophils and IgE. Moreover, the coadministration of QX008N with anti-IL-4R antibodies enhanced the inhibition of inflammatory mediator production triggered via costimulation in vitro. In mouse asthma models, the simultaneous blockade of TSLP and IL-4R using anti-TL4R and anti-TSLP surrogates surpassed the efficacy of monotherapy. To the best of our knowledge, the therapeutic effect of a combination of anti-TSLP and IL-4R antibodies in an asthma model has not yet been reported. ConclusionThese results furnish comprehensive preclinical evidence for QX008N as an innovative anti-TSLP therapeutic agent and provide a preliminary rationale for the development of combination therapies that simultaneously target the TSLP and IL-4R signaling pathways.

Use of stable isotope labeled (SIL) antibodies in cassette dosing to improve pharmacokinetics screening efficiency of ADCs with novel cytotoxic payloads

Stable isotope labelling by amino acids in cell culture (SILAC) is an established technique used in quantitative mass spectrometry (MS)-based proteomics. SILAC is also used to generate stable isotope labelled (SIL) antibodies for internal standards (IS) used in LC-MS/MS bioassays to improve quantitative robustness. Total antibody (TAb) is measured to evaluate pharmacokinetics (PK) of antibody drug conjugate (ADC) candidates measured by either ligand binding (LBA) or LC-MS/MS. Herein, we describe an application of SILAC, where multiple SIL combinations of an antibody are used for cassette dosing and PK evaluation. Our preclinical studies demonstrate SILAC-labelled ADC therapeutics did not alter antibody PK. Furthermore, with cassette dosing SIL antibodies exhibited comparable exposure to discretely administered unlabelled test articles in rats. In addition, SIL antibodies were conjugated to cytotoxic payloads to create SIL ADCs and cassette dosed in a cynomolgus monkey PK study and SIL ADCs yielded comparable PK results to discrete dosed unlabelled ADCs. In conclusion, SIL antibodies used with a cassette dosing strategy increases PK screening throughput of ADC candidates in preclinical species. Additionally, cassette dosing strategy further facilitates the responsible use of laboratory animals to achieve the three-Rs (Replacement, Reduction, and Refinement).

Observation of Leukocyte Differential in Macaca fascicularis

Observation of Leukocyte Differential in Macaca fascicularis

Liver-targeted Angptl4 silencing by antisense oligonucleotide treatment attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice.

Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid uptake from triglyceride-rich lipoproteins such as VLDL. While pharmacological inhibition of ANGPTL3 is being evaluated as lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aimed to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism. Mice were subcutaneously injected twice-weekly with saline or liver-targeted antisense oligonucleotides against Angptl3, Angptl4, both, or a scrambled oligonucleotide. Plasma lipid levels, VLDL clearance and hepatic VLDL production were determined, and atherosclerosis development was assessed. For toxicological evaluation, cynomolgus monkeys were treated with three dosages of liver-targeted ANGPTL4-silencing oligonucleotides.Liver-targeted Angptl4 silencing reduced plasma triglycerides (-48%) and total cholesterol (-56%), explained by higher VLDL-derived fatty acid uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, Angptl4 silencing reduced atherosclerotic lesion size (-86%) and improved lesion stability. Hepatic Angptl3 silencing similarly attenuated hyperlipidemia and atherosclerosis development. While Angptl3 and Angptl4 silencing lowered plasma triglycerides in the refed and fasted state, respectively, combined Angptl3/4 silencing lowered plasma triglycerides independent of nutritional state. In cynomolgus monkeys, anti-ANGPTL4 ASO treatment was well tolerated without adverse effects. Liver-targeted Angptl4 silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted ANGPTL4 silencing is well-tolerated in non-human primates. These data warrant further clinical development of liver-targeted ANGPTL4 silencing.

FZ-AD005, a Novel DLL3-Targeted Antibody-Drug Conjugate with Topoisomerase I Inhibitor, Shows Potent Antitumor Activity in Preclinical Models.

Delta-like ligand 3 (DLL3) is overexpressed in small cell lung cancer (SCLC) and has been considered an attractive target for SCLC therapy. Rovalpituzumab tesirine was the first DLL3-targeted antibody-drug conjugate (ADC) to enter clinical studies. However, serious adverse events limited progress in the treatment of SCLC with rovalpituzumab tesirine. In this study, we developed a novel DLL3-targeted ADC, FZ-AD005, by using DXd with potent cytotoxicity and a relatively better safety profile to maximize the therapeutic index. FZ-AD005 was generated by a novel anti-DLL3 antibody, FZ-A038, and a valine-alanine (Val-Ala) dipeptide linker to conjugate DXd. Moreover, Fc-silencing technology was introduced in FZ-AD005 to avoid off-target toxicity mediated by FcγRs and showed negligible Fc-mediated effector functions in vitro. In preclinical evaluation, FZ-AD005 exhibited DLL3-specific binding and demonstrated efficient internalization, bystander killing, and excellent in vivo antitumor activities in cell line-derived xenograft and patient-derived xenograft models. FZ-AD005 was stable in circulation with acceptable pharmacokinetic profiles in cynomolgus monkeys. FZ-AD005 was well tolerated in rats and monkeys. The safety profile of FZ-AD005 was favorable, and the highest nonseverely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of patients with SCLC.

Exogenous Growth Hormone Exacerbates Post-Irradiation Atherosclerosis in Susceptible Epicardial Coronary Arteries.

Cardiac exposure to ionizing radiation can damage both the microvasculature and coronary arteries, as well as increase the long-term risk of heart disease, myocardial fibrosis, and conduction abnormalities. Therapeutic agents capable of promoting recovery from radiation injury to the heart are limited. Growth hormone is linked to improved cardiac function following injury. Here, we leveraged a cynomolgus macaque model to determine the long-term outcomes of recombinant human growth hormone (rhGH) therapy on the heart following low-dose ionizing radiation. Macaques were exposed to 2 Gy radiation, treated with rhGH for one month, and assessed after 2 years. Overall, plasma lipid profile, cardiac function, and coronary artery disease were similar between rhGH and placebo treated animals. However, a subgroup of rhGH-treated animals exhibited more extensive atherosclerotic plaques in the coronary arteries. Together, these findings indicate that transient human growth hormone therapy subsequent to a single low dose of ionizing radiation involving the heart does not result in long-term changes to plasma cholesterol but may promote exacerbated coronary artery disease in a subset of individuals.