| 1. |
- Andersson, Hampus, et al.
(författare)
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Next-generation CD40 agonists for cancer immunotherapy
- 2024
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Ingår i: Expert Opinion on Biological Therapy. - 1471-2598. ; 24:5, s. 351-363
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Forskningsöversikt (refereegranskat)abstract
- Introduction: There is a need for new therapies that can enhance response rates and broaden the number of cancer indications where immunotherapies provide clinical benefit. CD40 targeting therapies provide an opportunity to meet this need by promoting priming of tumor-specific T cells and reverting the suppressive tumor microenvironment. This is supported by emerging clinical evidence demonstrating the benefits of immunotherapy with CD40 antibodies in combination with standard of care chemotherapy. Areas covered: This review is focused on the coming wave of next-generation CD40 agonists aiming to improve efficacy and safety, using new approaches and formats beyond monospecific antibodies. Further, the current understanding of the role of different CD40 expressing immune cell populations in the tumor microenvironment is reviewed. Expert opinion: There are multiple promising next-generation approaches beyond monospecific antibodies targeting CD40 in immuno-oncology. Enhancing efficacy is the most important driver for this development, and approaches that maximize the ability of CD40 to both remodel the tumor microenvironment and boost the anti-tumor T cell response provide great opportunities to benefit cancer patients. Enhanced understanding of the role of different CD40 expressing immune cells in the tumor microenvironment may facilitate more efficient clinical development of these compounds.
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| 2. |
- Gjörloff Wingren, Anette, et al.
(författare)
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TNFRSF9 (TNF receptor superfamily member 9)
- 2019
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Ingår i: Atlas of Genetics and Cytogenetics in Oncology and Haematology. - : INIST-CNRS. - 1768-3262. ; :9
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Forskningsöversikt (refereegranskat)abstract
- Review on TNFRSF9 (CD137), with data on DNA, on the protein encoded, and where the gene is implicated.
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| 3. |
- Hasterok, Sylwia, et al.
(författare)
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CD81 (Cluster of Differentiation 81)
- 2020
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Ingår i: Atlas of Genetics and Cytogenetics in Oncology and Haematology. - : Atlas of genetics and cytogenetics in oncology and haematology. - 1768-3262. ; :7
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Forskningsöversikt (refereegranskat)abstract
- Cluster of differentiation (CD81) is a type of protein, which is encoded by CD81 gene. Beside that CD81 is also known under other names such as Target of the Antiproliferative Antibody 1 (TAPA-1) and Tetraspanin-28 (TSPAN28). Location of CD81 is known to be on chromosome 11 (11p15.5), where it contains 15-20 bases in length. It is expressed mostly in cells of testis, ovary, endometrium, placenta, bone marrow, smooth muscles and others. The main function of the CD81 protein is to mediate signal transduction events, which are important for cells' development, activation, growth and motility. The CD81 gene is also known as a candidate for many malignancies because of its location. The characteristic feature of CD81 is that it is highly hydrophobic and contains a short N- and C-terminal cytoplasmic domains together with cytoplasmic cysteines, potential sites of palmitoylation as well as four transmembrane domains where they together hold the protein in a cell membrane. There are two CD81 isoforms, isoform 1 and isoform 2. Isoforms of CD81 are usually found in a tumor-suppressor region where they have a great impact on tumor development. There has always been a high interest in research on CD81 function in viral disease development. In fact, it is known that CD81 contributes in the development of diseases such as hepatitis C, malaria and various types of cancer. Since the complete effect of CD81 is unknown, further research and scientific methodology could potentially discover all possible functions and mechanisms regulated by the CD81 protein in human body.
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| 4. |
- Hägerbrand, Karin, et al.
(författare)
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Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies
- 2022
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Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Background Indications with poor T-cell infiltration or deficiencies in T-cell priming and associated unresponsiveness to established immunotherapies represent an unmet medical need in oncology. CD40-targeting therapies designed to enhance antigen presentation, generate new tumor-specific T cells, and activate tumor-infiltrating myeloid cells to remodel the tumor microenvironment, represent a promising opportunity to meet this need. In this study, we present the first in vivo data supporting a role for tumor-associated antigen (TAA)-mediated uptake and cross-presentation of tumor antigens to enhance tumor-specific T-cell priming using CD40×TAA bispecific antibodies, a concept we named Neo-X-Prime. Methods Bispecific antibodies targeting CD40 and either of two cell-surface expressed TAA, carcinoembryonic antigen-related cell adhesion molecule 5 (CEA) or epithelial cell adhesion molecule (EpCAM), were developed in a tetravalent format. TAA-conditional CD40 agonism, activation of tumor-infiltrating immune cells, antitumor efficacy and the role of delivery of tumor-derived material such as extracellular vesicles, tumor debris and exosomes by the CD40×TAA bispecific antibodies were demonstrated in vitro using primary human and murine cells and in vivo using human CD40 transgenic mice with different tumor models. Results The results showed that the CD40×TAA bispecific antibodies induced TAA-conditional CD40 activation both in vitro and in vivo. Further, it was demonstrated in vitro that they induced clustering of tumor debris and CD40-expressing cells in a dose-dependent manner and superior T-cell priming when added to dendritic cells (DC), ovalbumin (OVA)-specific T cells and OVA-containing tumor debris or exosomes. The antitumor activity of the Neo-X-Prime bispecific antibodies was demonstrated to be significantly superior to the monospecific CD40 antibody, and the resulting T-cell dependent antitumor immunity was directed to tumor antigens other than the TAA used for targeting (EpCAM). Conclusions The data presented herein support the hypothesis that CD40×TAA bispecific antibodies can engage tumor-derived vesicles containing tumor neoantigens to myeloid cells such as DCs resulting in an improved DC-mediated cross-priming of tumor-specific CD8 + T cells. Thus, this principle may offer therapeutics strategies to enhance tumor-specific T-cell immunity and associated clinical benefit in indications characterized by poor T-cell infiltration or deficiencies in T-cell priming.
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| 5. |
- Nyesiga, Barnabas, et al.
(författare)
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CD22 (CD22 molecule)
- 2020
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Ingår i: Atlas of Genetics and Cytogenetics in Oncology and Haematology. - : INIST-CNRS. - 1768-3262. ; :12
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Forskningsöversikt (refereegranskat)abstract
- Sialic acid binding immunoglobulin-type lectin (Siglec) family are inhibitory receptors with diverse roles in the immune system. Siglec family contains 14 members in human and 9 in murine. Differentially expressed on various white blood cells. Here in this review we are focusing on CD22, also known as Sialic Acid-Binding Ig-Like Lectin 2 (Siglec-2). CD22 gene is located on 19q13.12 and is encoding a 140 kD type I transmembrane glycoprotein on the surface of B cells and is part of the immunoglobulin (Ig) superfamily and has been found only on B cells. CD22 has been shown to play a major role in establishing a baseline level of B-cell inhibition, and thus is a critical determinant of homeostasis in humoral immunity.
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| 6. |
- Nyesiga, Barnabas, et al.
(författare)
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PIP5K1A (phosphatidylinositol-4-phosphate 5-kinase type 1 alpha)
- 2018
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Ingår i: Atlas of Genetics and Cytogenetics in Oncology and Haematology. - : INIST-CNRS. - 1768-3262. ; 22:2, s. 41-43
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Forskningsöversikt (refereegranskat)abstract
- Review on PIP5K1A, with data on DNA, on the protein encoded, and where the gene is implicated.
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| 7. |
- Nyesiga, Barnabas, et al.
(författare)
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RUBY® - a tetravalent (2+2) bispecific antibody format with excellent functionality and IgG-like stability, pharmacology and developability properties
- 2024
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Ingår i: mAbs. - : Taylor & Francis. - 1942-0862 .- 1942-0870. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite the large number of existing bispecific antibody (bsAb) formats, the generation of novel bsAbs is still associated with development and bioprocessing challenges. Here, we present RUBY, a novel bispecific antibody format that allows rapid generation of bsAbs that fulfill key development criteria. The RUBYTM format has a 2 + 2 geometry, where two Fab fragments are linked via their light chains to the C-termini of an IgG, and carries mutations for optimal chain pairing. The unique design enables generation of bsAbs with mAb-like attributes. Our data demonstrate that RUBY bsAbs are compatible with small-scale production systems for screening purposes and can be produced at high yields (>3 g/L) from stable cell lines. The bsAbs produced are shown to, in general, contain low amounts of aggregates and display favorable solubility and stress endurance profiles. Further, compatibility with various IgG isotypes is shown and tailored Fc gamma receptor binding confirmed. Also, retained interaction with FcRn is demonstrated to translate into a pharmacokinetic profile in mice and non-human primates that is comparable to mAb controls. Functionality of conditional active RUBY bsAbs is confirmed in vitro. Anti-tumor effects in vivo have previously been demonstrated, and shown to be superior to a comparable mAb, and here it is further shown that RUBY bsAbs penetrate and localize to tumor tissue in vivo. In all, the RUBY format has attractive mAb-like attributes and offers the possibility to mitigate many of the development challenges linked to other bsAb formats, facilitating both high functionality and developability.
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| 8. |
- Wingren, Anette Gjörloff, et al.
(författare)
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CDK2 (cyclin dependent kinase 2)
- 2018
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Ingår i: Atlas of Genetics and Cytogenetics in Oncology and Haematology. - : INIST-CNRS. - 1768-3262. ; 22:9, s. 369-374
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Forskningsöversikt (refereegranskat)abstract
- Review on CDK2, with data on DNA, on the protein encoded, and where the gene is implicated.
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