46 research outputs found
Site-selective multi-porphyrin attachment enables the formation of a next-generation antibody-based photodynamic therapeutic
Herein we present a significant step towards next-generation antibody-based photodynamic therapeutics. Site-selective modification of a clinically relevant monoclonal antibody, with a serum-stable linker bearing a strained alkyne, allows for the controlled Cu-free âclickâ assembly of an in vitro active antibody-based PDT agent using a water soluble azide porpyhrin
Recurrent Linear Dermatosis in a 9-Year-Old Boy
International audienc
Regioselective and stoichiometrically controlled conjugation of photodynamic sensitizers to a HER2 targeting antibody fragment
The rapidly increasing interest in the synthesis of antibodyâdrug conjugates as powerful targeted anticancer agents demonstrates the growing appreciation of the power of antibodies and antibody fragments as highly selective targeting moieties. This targeting ability is of particular interest in the area of photodynamic therapy, as the applicability of current clinical photosensitizers is limited by their relatively poor accumulation in target tissue in comparison to healthy tissue. Although synthesis of porphyrinâantibody conjugates has been previously demonstrated, existing work in this area has been hindered by the limitations of conventional antibody conjugation methods. This work describes the attachment of azide-functionalized, water-soluble porphyrins to a tratuzumab Fab fragment via a novel conjugation methodology. This method allows for the synthesis of a homogeneous product without the loss of structural stability associated with conventional methods of disulfide modification. Biological evaluation of the synthesized conjugates demonstrates excellent selectivity for a HER2 positive cell line over the control, with no dark toxicity observed in either case
Synthesis of a novel HER2 targeted aza-BODIPYâantibody conjugate: synthesis, photophysical characterisation and in vitro evaluation
We herein report the synthesis and analysis of a novel aza-BODIPYâantibody conjugate, formed by controlled and regioselective bioconjugation methodology. Employing the clinically relevant antibody, which targets HER2 positive cancers, represents the first example of an antibody targeting strategy for this class of near-IR emitting fluorophore. The NIR fluorescence and binding properties were validated through in vitro studies using live cell confocal imaging
Modular Chemical Construction of IgG-like Mono- and Bispecific Synthetic Antibodies (SynAbs)
In recent years there has been rising interest in the
field of proteinâprotein conjugation, especially related to bispecific
antibodies (bsAbs) and their therapeutic applications. These
constructs contain two paratopes capable of binding two distinct
epitopes on target molecules and are thus able to perform complex
biological functions (mechanisms of action) not available to
monospecific mAbs. Traditionally these bsAbs have been
constructed through protein engineering, but recently chemical
methods for their construction have started to (re)emerge. While
these have been shown to offer increased modularity, speed, and for
some methods even the inherent capacity for further functionalization (e.g., with small molecule cargo), most of these approaches lacked the ability to include a fragment crystallizable (Fc) modality.
The Fc component of IgG antibodies offers effector function and increased half-life. Here we report a first-in-class disulfide
rebridging and click-chemistry-based method for the generation of Fc-containing, IgG-like mono- and bispecific antibodies. These
are in the FcZ-(FabX)-FabY format, i.e., two distinct Fabs and an Fc, potentially all from different antibodies, attached in a
homogeneous and covalent manner. We have dubbed these molecules synthetic antibodies (SynAbs). We have constructed a T cellengager (TCE) SynAb, FcCD20-(FabHER2)-FabCD3, and have confirmed that it exhibits the expected biological functions, including the
ability to kill HER2+ target cells in a coculture assay with T cells
Merkel Cell Polyomavirus Strains in Patients with Merkel Cell Carcinoma
We investigated whether Merkel cell carcinoma (MCC) patients in France carry Merkel cell polyomavirus (MCPyV) and then identified strain variations. All frozen MCC specimens and 45% of formalin-fixed and paraffin-embedded specimens, but none of the non-MCC neuroendocrine carcinomas specimens, had MCPyV. Strains from France and the United States were similar
Relationship between childhood physical abuse and clinical severity of treatment-resistant depression in a geriatric population
Introduction: We assessed the correlation between childhood maltreatment (CM) and severity of depression in an elderly unipolar Treatment-Resistant Depression (TRD) sample. Methods: Patients were enrolled from a longitudinal cohort (FACE-DR) of the French Network of Expert TRD Centres. Results: Our sample included 96 patients (33% of the overall cohort) aged 60 years or above, with a mean age of 67.2 (SD = 5.7). The majority of the patients were female (62.5%). The Montgomery and Asberg Depression Rating Scale (MADRS) and Quick Inventory Depression Scale-Self Report (QIDS-SR) mean scores were high, 28.2 (SD = 7.49) [MADRS score range: 0â60; moderate severityâ„20, high severityâ„35] and 16.5 (SD = 4.94) [IDS-SR score range: 0â27; moderate severityâ„11, high severityâ„16], respectively. Mean self-esteem scores were 22.47 (SD = 6.26) [range 0â30]. In an age- and sex-adjusted model, we found a positive correlation between childhood trauma (CTQ scores) and depressive symptom severity [MADRS (ÎČ = 0.274; p = 0.07) and QIDS-SR (ÎČ = 0.302; p = 0.005) scores]. We detected a statistically significant correlation between physical abuse and depressive symptom severity [MADRS (ÎČ = 0.304; p = 0.03) and QIDS-SR (ÎČ = 0.362; p = 0.005) scores]. We did not observe any significant correlation between other types of trauma and depressive symptom severity. We showed that self-esteem (Rosenberg scale) mediated the effect of physical abuse (PA) on the intensity of depressive symptoms [MADRS: b = 0.318, 95% BCa C.I. [0.07, 0.62]; QIDS-SR: b = 0.177, 95% BCa C.I. [0.04, 0.37]]. Preacher & Kellyâs Kappa Squared values of 19.1% (k2 = 0.191) and 16% (k2 = 0.16), respectively for the two scales, indicate a moderate effect. Conclusion: To our knowledge, this is the first study conducted in a geriatric TRD population documenting an association between childhood trauma (mainly relating to PA) and the intensity of depressive symptoms
Light-driven reductive cleavage of sulfonamides promoted by thiourea organophotosensitizers
We have developed a practical method to perform the reductive photocleavage of sulfonamides using thioureas as organophotocatalysts. This transformation, which tolerates a variety of substrates, occurs under mild reaction conditions in the presence of tetrabutylammonium borohydride as a reducing agent. Experimental and theoretical mechanistic investigations complete the study, shedding light on the nature of the active species involved in the photocatalytic process
Yellowish Nodules on the Vulva in a 6-Year-Old Girl: A Quiz
International audienc