Inference of molecular structure for characterization and improvement of clinical grade immunocytokines

Ongaro, Tiziano; Guarino, Salvatore; Scietti, Luigi; Palamini, Martina; Wulhfard, Sarah; Neri, Dario; Villa, Alessandra; Forneris, Federico

doi:10.1016/j.jsb.2021.107696

Cited by 3 publications

(4 citation statements)

References 59 publications

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“…We introduce a new description of diabody conformations by calculating the centers of mass (COM) for each V H and V L domain and projecting them on a unit sphere. When applying this metric on 31 crystal structures of the PDB, 38 , 55 , 64 , 95 , 96 , 97 , 98 , 99 , 100 , 101 we observe a clustering of the structures (Figure 5 ). We visually assigned the structures to five clusters, based on their V H and V L domains in our representation and find two major groups, cluster 1 with 22 structures and cluster 2 with 4 structures, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…In our representation, the structure with the PDB code 7AH1 101 is very different to the others and can be classified as sole member of cluster 5. This structure was obtained by crystallizing a L19 diabody fragment, covalently bound to IL12.…”

Section: Resultsmentioning

confidence: 99%

“…Kim et al hypothesized the remarkable difference to other known diabody structures to be caused by an arginine at position H83. 38 In our representation, the structure with the PDB code 7AH1 101 is very different to the others and can be classified as sole member of cluster 5. This structure was obtained by crystallizing a L19 diabody fragment, covalently bound to IL12.…”

Section: Sphere Projectionmentioning

confidence: 99%

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Cross‐linking disulfide bonds govern solution structures of diabodies

et al. 2023

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In the last years, antibodies have emerged as a promising new class of therapeutics, due to their combination of high specificity with long serum half‐life and low risk of side‐effects. Diabodies are a popular novel antibody format, consisting of two Fv domains connected with short linkers. Like IgG antibodies, they simultaneously bind two target proteins. However, they offer altered properties, given their smaller size and higher rigidity. In this study, we conducted the—to our knowledge—first molecular dynamics (MD) simulations of diabodies and find a surprisingly high conformational flexibility in the relative orientation of the two Fv domains. We observe rigidifying effects through the introduction of disulfide bonds in the Fv–Fv interface and characterize the effect of different disulfide bond locations on the conformation. Additionally, we compare VH–VL orientations and paratope dynamics between diabodies and an antigen binding fragment (Fab) of the same sequence. We find mostly consistent structures and dynamics, indicating similar antigen binding properties. The most significant differences can be found within the CDR‐H2 loop dynamics. Of all CDR loops, the CDR‐H2 is located closest to the artificial Fv–Fv interface. All examined diabodies show similar VH–VL orientations, Fv–Fv packing and CDR loop conformations. However, the variant with a P14C‐K64C disulfide bond differs most from the Fab in our measures, including the CDR‐H3 loop conformational ensemble. This suggests altered antigen binding properties and underlines the need for careful validation of the disulfide bond locations in diabodies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Sphere Projectionmentioning

confidence: 99%

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Cross‐linking disulfide bonds govern solution structures of diabodies

et al. 2023

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“…These "immune cytokines" include NHS-IL2 and L19-IL2, etc. [36][37][38]. L19-IL2 only works in EDB-expressing tumors, which largely depends on the presence of CD81 cytotoxic T cells [39,40].…”

Section: Preclinical Study Of Immunotherapy Combined With Radiotherapymentioning

confidence: 99%

Combinations of radiotherapy with immunotherapy in cervical cancer

Yang

Ren

2022

J. Cancer

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Immunotherapy serves as another effective cancer treatment apart from surgery, chemoradiotherapy, and targeted drug therapy. Radiotherapy combined with immunotherapy has significantly improved the effective cure rate for patients in several clinical trials. It subverted the traditional view that radiotherapy kills immune cells and has immunosuppressive effects, indicating a synergistic effect of radiotherapy and immunotherapy. In this article, we reviewed and summarized the molecular mechanism of the combined use of radiotherapy and immunotherapy, as well as the clinical treatment and safety of the combination of the two. We describe the rationale for the integration of radiotherapy and immunotherapy in patients with cervical cancer, present safety and efficacy data that support this combination strategy, and highlight unanswered question sand future research needs. Besides, this study can be referenced for clinicians to guide subsequent clinical medicine.

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Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview

Boersma,

Poinot,

Pommier

2024

Pharmaceutics

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Cytokines are immune modulators which can enhance the immune response and have been proven to be an effective class of immunotherapy. Nevertheless, the clinical use of cytokines in cancer treatment has faced several challenges associated with poor pharmacokinetic properties and the occurrence of adverse effects. Immunocytokines (ICKs) have emerged as a promising approach to overcome the pharmacological limitations observed with cytokines. ICKs are fusion proteins designed to deliver cytokines in the tumor microenvironment by taking advantage of the stability and specificity of immunoglobulin-based scaffolds. Several technological approaches have been developed. This review focuses on ICKs designed with the most impactful cytokines in the cancer field: IL-2, TNFα, IL-10, IL-12, IL-15, IL-21, IFNγ, GM-CSF, and IFNα. An overview of the pharmacological effects of the naked cytokines and ICKs tested for cancer therapy is detailed. A particular emphasis is given on the immunomodulatory effects of ICKs associated with their technological design. In conclusion, this review highlights active ways of development of ICKs. Their already promising results observed in clinical trials are likely to be improved with the advances in targeting technologies such as cytokine/linker engineering and the design of multispecific antibodies with tumor targeting and immunostimulatory functional properties.

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Inference of molecular structure for characterization and improvement of clinical grade immunocytokines

Cited by 3 publications

References 59 publications

Cross‐linking disulfide bonds govern solution structures of diabodies

Cross‐linking disulfide bonds govern solution structures of diabodies

Combinations of radiotherapy with immunotherapy in cervical cancer

Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview

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