Abstract
Agonist OX40 antibodies have shown promising pre-clinical activities, but their clinical activities have been limited thus far. Several reasons may account for this limited clinical ...activity, including sub-optimal antibody design, dose selection, and lack of a biomarker strategy for indication selection and patient enrichment. Previous clinical trials selected doses that maximized receptor occupancy, but some patients responded at lower doses, indicating nuances to choosing the correct therapeutic doses for an agonist antibody. In addition, preclinical work has demonstrated a so-called “hook” effect whereby agonist activity decreases at higher concentrations, which further emphasizes the need to develop a novel anti-OX40 therapeutic antibody that addresses the previously encountered challenges.
HFB301001 is a novel human IgG1 agonist antibody that binds to a unique epitope on OX40. This allows for agonistic activity that does not compete with the endogenous OX40 ligand. Relative to other clinical stage OX40 antibodies, HFB301001 has reduced OX40 downregulation following co-stimulation of T cells, and it has demonstrated superior in vivo anti-tumor activity and pharmacodynamic immune modulation in a human OX40 knock-in mouse model. HFB301001 is well tolerated in cynomolgus monkeys. To progress into clinical studies, we have determined human dose projections for clinical evaluation of HFB301001 using PKPD modeling, serum exposure in non-human primates, antitumor efficacy in mouse models and immune cell pharmacodynamics. We also took advantage of Fc variants to delineate the relative contributions of Treg depletion versus enhancing T cell activity by agonism to efficacy of HFB301001. To further enhance probability of success (POS) in clinical studies, we are applying our single-cell Drug Intelligent Science (DIS™) platform to rationally identify cancer indications and to define novel predictive response biomarkers. We have used single-cell profiling to identify unique tumor-infiltrating T cell signatures that may help identify patients more likely to response to HFB301001 treatment, inform indication selection, and establish a patient stratification biomarker strategy. Finally, we show here our phase I trial design for HFB301001 that implements these findings.
In conclusion, HFB301001 is a highly differentiated therapeutic antibody which is well positioned to enter a global, multi-center Phase I clinical trial to explore optimal biologically active dose and evaluate predictive biomarker hypotheses. Here, we present results supporting the rationale for indication selection, biomarker identification, dose selection, and phase I clinical trial design.
Citation Format: Ross Fulton, Jinping Gan, Yun-Yueh Lu, Julianna Crivello, Zachery Duda, Zhiyuan Wang, Rebecca Silver, Alexandra Staskus, Charina Ortega, Sami Ellouze, Carine George, Sophie Foulon, Wenhua Xu, Xing Cai, Joyce Pi, Dean Lee, Monika Manne, Ruina Jin, Yuan Wang, Hongkai Zhang, Nicola Beltraminelli, Francisco Adrian, Robert Petit, Liang Schweizer, Andreas Raue. Clinical approach and biomarker strategy for HFB301001, a novel OX40 agonistic antibody abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1882.
Abstract
Despite the success of immune check point inhibition, identification of other pathways capable of modulating the immune response against the tumor remains challenging. T-cell co-stimulation ...has been investigated with limited clinical success so far due in part to the fine tuning required for agonist antibodies against those co-stimulatory receptors and to the lack of biomarkers to facilitate the selection of patients likely to benefit from T-cell co-stimulation. TNFR2 belongs to the TNFR family of costimulatory molecules, and its expression on tumor infiltrating lymphocytes across a wide range of tumors make it an attractive target for T-cell co-stimulation. Recently, we identified HFB200301, an anti-TNFR2 antibody with Fc-independent agonist activity that does not block TNFR2 interaction with TNFα. HFB200301 activates CD4+, CD8+ T cells, and NK cells in vitro. In vivo, HFB200301 demonstrated potent single agent anti-tumor activity in syngeneic tumor models and can further increase the antitumor activity in combination with PD-1 blockade.
To understand the immunological basis for the anti-tumor efficacy of HFB200301, we investigated the pharmacodynamic effects of HFB200301 in syngeneic mouse tumor models, including immuno-phenotyping and receptor occupancy of tumor infiltrating cells. In hTNFR2 knock-in mice bearing MC38 tumors, HFB200301 induces expansion of CD4+ and CD8+ T cells, and NK cells in the tumor micro-environment without affecting regulatory T cell numbers. We also demonstrate that the anti-tumor efficacy of HFB200301 is correlated with receptor occupancy and circulating soluble TNFR2 in a dose-dependent manner in this model.
To discover predictive biomarkers of response to HFB200301, we used primary tumor samples and our proprietary Drug Intelligent Science (DIS™) single-cell platform to establish an immune-related signature. Single-cell RNA sequencing and clonotype barcoding of ex-vivo tumor cultures treated with HFB200301 were used to identify unique T cell profiles with a T cell centric gene panel. These unique T cell profiles may help identifying patients more likely to respond to HFB200301 treatment.
In summary, HFB200301 exhibits a unique mechanism of action mainly relying on its agonistic activity on several effector cell types in tumor micro-environment that we expect will benefit a patient population selected with a unique biomarker signature. HFB200301 is currently in preclinical development and a biomarker-driven Phase 1 clinical study is projected for 2021.
Citation Format: Shuo Wei, Ross Fulton, Yun-Yueh Lu, Qian Zhang, He Zhou, Andreas Raue, Mingjie Chen, Wenhua Xu, Xing Cai, Juliana Crivello, Zachary Duda, Zhiyuan Wang, Rebecca Silver, Alexandra Staskus, Charina Ortega, Sami Ellouze, Carine George, Sophie Foulon, Dean Lee, Monika Manne, Nicola Beltraminelli, Jinping Gan, Francisco Adrian, Liang Schweizer, Jennifer Watkins-Yoon. Mechanism of action and biomarker strategy for HFB200301, an anti-TNFR2 agonist antibody for the treatment of cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1883.
Cancer du sein et sexualité Masmoudi, S.; Ellouze, F.; Abidi, S. ...
Psycho-oncologie,
06/2019, Letnik:
13, Številka:
2
Journal Article
Recenzirano
L’influence du cancer du sein et de ses traitements sur la sexualité reste encore très peu explorée en Tunisie. Dans ce travail, on se propose de rapporter les difficultés et le vécu sexuels de deux ...femmes tunisiennes présentant un cancer du sein. À travers ces deux vignettes, il s’avère que les causes sont multiples et intriquées, on pourrait schématiquement les classer en cinq catégories : difficultés dans la communication avec le médecin traitant, croyances erronées, réaction dépressive, iatrogénie et modification de l’image du corps, troubles de la communication au sein du couple. Maintenir une image de soi positive, se sentir encore féminine et rester sexuellement attirante contribuent au bien-être des femmes confrontées au cancer du sein.
The influence of breast cancer treatment on sexuality remain very little explored in Tunisia. In this study our purpose was looked for sexual trouble among two Tunisian women with a breast cancer. Our two patients have sexual troubles. We have classified the sexual troubles’ causes in five categories: communication troubles with the attending physician, distortion in beliefs about cancer, sexuality or treatment, depressive reaction to the disease or treatment, modification of the body shape and communication troubles within the couple. Remaining to be sexually attractive was important for women with breast cancer
This study aimed at tracking the prevalence of body image disorder in a population of Tunisian women followed for breast cancer and the factors associated with it.
The cross-sectional study was ...conducted at Salah-Azaiez Institute in Tunis, over a period of four months. One hundred outpatients followed for confirmed breast cancer were recruited. The questionnaire targeted the women's sexuality and their couple relationships, along with their socio-demographic, clinical, and therapeutic characteristics. The scales used were BIS, HADS, and FSFI.
The prevalence of body image disorder according to BIS was 45% with an average of 11.5±11.2 among the interrogated patients, 24.7% of which reported an alteration in their couple relationships and 47% in their sexual relations. In univariate analysis, body image disorder was associated with family support, change in couple relationship, depression and anxiety. Body image disorder and sexual dysfunction were interrelated: each of them fostered the prevalence of the other. Multivariate analysis showed that occupational activity was an independent predictor and the absence of anxiety an independent protective factor. Body image disorder was an independent predictive factor of depression and anxiety.
The quality of couple relation and sexuality, along with the impact of the patient's surrounding are decisive for the protection or alteration of her body image.
Biermer disease or pernicious anemia is an autoimmune atrophic gastritis characterized by the lack of secretion of gastric intrinsic factor. This leads to an insufficient absorption of vitamin B12 in ...the ileum. Clinical manifestations are mainly hematologic. Neuropsychiatric manifestations are known but are less frequent especially early in the disease. Inaugural neuropsychiatric arrays are rare and various thus making diagnosis difficult. In this article, we report through two clinical cases different neuropsychiatric manifestations revealing pernicious anemia. Mrs. C.O., aged 56, presented after surgery for gallstones, an acute psychiatric array associated with gait disorders. She had no history of neurological or psychiatric problems. The psychiatric interview revealed delirious syndrome, depressive symptoms and anxiety. Neurological examination noted a flaccid paraplegia with peripheral neuropathic syndrome and myoclonus in the upper limbs. At the full blood count, a macrocytosis (VGM: 112.2fl) without anemia was found. The level of vitamin B12 in the blood was low. Cerebro-spinal MRI was suggestive of a neuro-Biermer and showed hyper signal in the cervical cord on T2-weighted sagittal section. In axial section, hyper signal appears at the posterior columns in the form of V. There were no brain abnormalities. A sensorimotor axonal polyneuropathy was diagnosed. The patient received vitamin B12 intramuscularly for ten days associated with neuroleptic treatment. Mrs. R.M., aged 40, was brought to the psychiatry consultation for acute behavioral disorders progressively worsening over a month. An anxiety syndrome, depressive syndrome and delirious syndrome were identified. Neurological examination showed a posterior cordonal syndrome with quadripyramidal syndrome. Full blood count showed a macrocytic anemia. Serum B12 level was collapsed. Cerebro-spinal MRI was normal. She received vitamin B12 with clinical and biological improvement. Features of pernicious anemia vary according to studies and age range. Digestive and hematological manifestations are well known. Neurological and psychiatric manifestations of pernicious anemia were also described in the early literature. They can be the initial symptoms or the only ones. However, inaugural neuropsychiatric features are often unrecognized. The most common psychiatric symptoms were depression, mania, psychotic symptoms, cognitive impairment and obsessive compulsive disorder. Neurological involvement includes mainly combined spinal sclerosis, peripheral neuropathy and dementia. Cerebellar ataxia and movement disorders are reported less often. Severity of neuropsychiatric features and therapeutic efficacy depends on the duration of signs and level of B12 deficiency. Macrocytic anemia may lack. Neuropsychiatric manifestations could be isolated or be the first manifestation of vitamin deficiency and occur without any hematological or gastrointestinal context. Pernicious anemia and serum B12 assay should be discussed in all patients with organic mental disorders, atypical psychiatric symptoms and fluctuation of symptomatology. Nevertheless, B12 level could be normal in genuine pernicious anemia diseases and macrocytic anemia may lack. Substitutive vitaminotherapy is required when diagnosis is strongly suspected and etiologic assessment is negative.
Abstract Failure of the anterior neuropore can lead to three main types of anomalies: nasal dermal sinus, encephalocele and nasal glioma or heterotopia. In this report, we describe a case of ...intracranial and extracranial glial heterotopia that probably resulted from a common failure of anterior neuropore development. We describe the prenatal radiological assessment based on ultrasound and MRI results, and consider their limitation for early fetal diagnosis. We also discuss the embryogenesis and the possible pathogenic mechanisms involved.
Although Modern Standard Arabic is taught in schools and used in written communication and TV/radio broadcasts, all informal communication is typically carried out in dialectal Arabic.In this work, ...we focus on the design of speech tools and resources required for the development of an Automatic Speech Recognition system for the Tunisian dialect.The development of such a system faces the challenges of the lack of annotated resources and tools, apart from the lack of standardization at all linguistic levels (phonological, morphological, syntactic and lexical) together with the mispronunciation dictionary needed for ASR development.In this paper, we present a historical overview of the Tunisian dialect and its linguistic characteristics. We also describe and evaluate our rule-based phonetic tool. Next, we go deeper into the details of Tunisian dialect corpus creation. This corpus is finally approved and used to build the first ASR system for Tunisian dialect with a Word Error Rate of 22.6%.
Gluten extracted from fresh pasta by-products (PG) was enzymatically hydrolyzed by two different commercial proteases (Alcalase 2.4 L and Pancreatin) to different degrees of hydrolysis (DH 2.0, 4.0 ...and 8.0%). Commercial gluten (CG) was used as reference. The evaluation of functional properties of hydrolyzates from pasta gluten (PGH) and commercial gluten (CGH) showed that Pancreatin hydrolyzates had the highest emulsifying capacities. Regarding the foaming activity, all hydrolyzates performed better than unhydrolyzed gluten. PGH and CGH were added to wheat flour (1%) and their effects on dough rheology were studied. Most hydrolyzates with DH 8% increased dough thermal stability and elasticity during mixing, accelerated the denaturation rate of the protein network, and delayed the gelatinization speed of starch as the temperature increased. Texture profiles and specific volumes of breads from low quality wheat flour with added Pancreatin hydrolyzates (DH 8%) were comparable to those of breads from high quality flour. This showed the potential suitability of PGH and CGH as bread improvers.
•Hydrolysates of extracted gluten (PGH) was obtained by Alcalase or Pancreatin.•Emulsifying and foaming properties of PGH were higher than native gluten.•PGH incorporated in low breadmaking flour quality improved its rheological properties.•Due to its interesting technological properties PGH can be used as bread improver.
Bipolar disorder (BD) etiopathogenesis is still not well elucidated. It has recently been proven that 25-hydroxy vitamin D (25OHD) has an anti-inflammatory and neuroprotective role. Our objectives ...were to measure 25OHD plasma levels in patients with BD in acute decompensation and compare them with patients with schizophrenia (SCZ) or schizoaffective disorder (SAD) and with healthy controls.
This is a cross-sectional case-control study including male inpatients with a decompensation of their disease who were diagnosed with BD, SCZ or SAD according to DSM-5 criterias. The control group was constituted by unrelated healthy subjects, age-and-sex matched.
The 25OHD level was significantly higher only in patients with BD compared to controls. 25OHD was also positively correlated to the PANSS scale (r = 0.282, p < 0.001) and to different MOCA scores (r = 0.326, p = 0.006) as well as aspects related to abstraction, attention and memory capacity. Multivariate analysis found that BD acute decompensation was independently related to the rise in plasma 25OHD (p = 0.012; OR =1.157, 1.032 -1.297).
Our study shows that BD acute decompensation is associated with the rise in plasma 25OHD synthesis. However, the vitamin D dosage relevance as a biomarker of this disease warrants a verification in other studies.
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