The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

TRUST4 is now certified as AIRR-compliant

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The AIRR Community is excited to announce that TRUST4 has been certified as compliant with the AIRR-C v1.0 standard for AIRR-Seq software tools. TRUST4 (Tcr Receptor Utilities for Solid Tissue 4) is a tool for assembling BCRs and TCRs from bulk and single-cell RNA-Seq data.

In an effort to enable rigorous and reproducible immune repertoire research at the largest scale possible, the AIRR-C Software Working Group has established a standard to validate software tools using the AIRR-C Standards and meeting a series of interoperability and quality criteria. Developers interested in certifying their tools should complete the checklist and submit it to the AIRR-C Software Working Group for evaluation and ratification by its members.

More details can be found at the website AIRR Software WG – Guidance for AIRR Software Tools.

All compliant tools will be issued a badge and listed on the website AIRR Software WG – List of Tools Certified as Compliant. The list currently includes SONAR, ImmuneDB, Scirpy, Immcantation, CompAIRR, ImmuneML and Dandelion in addition to TRUST4.

IgE Class Antibody Immunotherapy for Solid Tumors

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Summary written by Alicia Chenoweth, PhD, King’s College London; Image from Ref. 7.

Antibody Engineering & Therapeutics, held in December 2022, offered many opportunities to hear exciting and informative presentations by experts in the field, including Professor Sophia Karagiannis from King’s College London, who discussed “IgE Class Antibody Immunotherapy for Solid Tumours”.

Although IgE is notorious for its role in allergic pathogenesis and anti-parasitic immune responses, there is increasing evidence that IgE may also play a role in protection against cancer. IgE deficiency is associated with increased risk of cancer, while higher total serum IgE levels may be protective against certain forms of cancer [1]. Thus, IgE biology may be of interest to cancer therapy. There are many desirable properties of IgE over the traditionally used IgG for cancer therapeutics, such as engaging powerful FceR receptors that are not shared with other classes of Ig, a very high-affinity for its high-affinity receptor FceRI which removes the need for immune complex formation allowing lower-expressing antigens to be targeted, high tissue penetration and persistence (around 1-2 weeks half-life in tissues, compared to a few days for IgG), and the lack of inhibitory receptors.

For IgE therapies, it is important to select a target which is highly expressed in tumor tissue and lowly expressed in normal tissues to enhance safety, as well as making sure that the antigen is not shed in large, multivalent formats in the circulation. Folate receptor alpha (FRa) was selected as a potential target for IgE immunotherapy, as it is overexpressed in several solid tumors, including ovarian cancer, basal breast cancer, and mesotheliomas, while also demonstrating low expression in normal tissues by transcriptomic and immunohistochemical studies [2]. An anti-FRa antibody that had already been in clinical trials and showed safety and efficacy as an IgG format was selected to engineer into an IgE format.

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Intratumorally Anchored Cytokine Therapy

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Summary written by Czeslaw Radziejewski, Ph.D.

Antibody Engineering & Therapeutics, held in December 2022, offered many opportunities to hear exciting and informative presentations by experts in the field, including K. Dane Wittrup, Professor of Chemical Engineering and Biological Engineering, Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, who discussed “Intratumorally Anchored Cytokine Therapy”.

As a result of advances in interventional radiologic, endoscopic, and laparoscopic procedures, most cancer tissues can now be accessed for a local injection directly into the tumor, with the aim of triggering an immune response that will act globally against cancer. Because of their anti-tumor activity and synergistic behavior, cytokines such as IL-2, IL-12, and interferons are currently considered for intratumoral therapies. Cytokine exposure is spatiotemporally programmed during immune responses, which means cytokines are present at certain places at certain times and in a particular order. As therapeutic agents, optimally they should be supplied in particular tissues at particular times for a specific duration. Direct cytokine injection into tumors has been attempted, but this approach was previously unsuccessful because of leakages out of the target tissue and systemic toxicity.

In his presentation, Prof. Wittrup described two strategies to localize cytokines to the target tissue that could allow for efficacious levels to be reached without overall toxicity. Both methods take advantage of retaining cytokines at the site of injection through interaction with collagen. [1,2,3] One approach relies on anchoring cytokines to the collagen-binding extracellular protein Lumican and the other relies on anchoring cytokines to the vaccine adjuvant Alum (aluminum hydroxide). Alum forms clusters of nanocrystals that are positively charged, which, when injected, tend to stay at the injection site. Because phosphorylated proteins bind very strongly to Alum, cytokines are fused to a proprietary peptide called alum peptide. The construct is co-expressed with kinase Fam20C, which attaches multiple phosphates to the peptide. Phosphorylated cytokine is then mixed with Alum and injected into the tumor site. Lumican binds to collagen type 1 and type 4, and Alum binds to collagen type 1. Lumican anchored molecules stay in place for 2 to 3 days. Alum anchoring increases tumor exposure to more than three weeks.

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Efgartigimod: A Novel FcRn Antagonist in the Treatment of Autoimmune Diseases

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Summary written by Alicia Chenoweth, PhD, King’s College London

Antibody Engineering & Therapeutics, held in December 2022, offered many opportunities to hear exciting and informative presentations by experts in the field, including Dr. Hans de Haard, Chief Scientific Officer at argenx.

Dr. de Haard’s talk, Efgartigimod: A Novel FcRn Antagonist in the Treatment of Autoimmune Diseases, detailed the mechanism of action and clinical trial results of the FcRn antagonist efgartigimod. Efgartigimod is a human IgG1 Fc fragment with five “Abdeg” mutations (M252Y, S254T, T256E, H433K, N434F) to increase its affinity for FcRn at both low pH and neutral pH (1,2). It is designed to outcompete the binding of serum IgG for FcRn, leading to degradation of the unbound IgG and recycling of efgartigimod back to the surface of the cell to be released back into circulation.

Dr. de Haard discussed the findings of a recent publication in which the biochemical, structural, and in vivo properties of efgartigimod and a full-length antibody counterpart containing the same Abdeg mutations were compared (3). Crystallographic studies of FcRn in complex with the full-length antibody demonstrated that the antigen-binding fragment projects towards the membrane, leading to a potential steric clash hindering binding. This hypothesis was confirmed using a bioassay measuring receptor occupancy, showing that efgartigimod gave a better FcRn occupancy and had improved uptake compared to the full-length antibody. Furthermore, in cynomolgus monkeys, the Fc fragment gave a much faster clearance of tracer antibody and a more potent pharmacodynamic effect compared to full-length antibody. Thus, the Fc fragment was determined to be the better performing FcRn antagonist over the full-length antibody due to improved blocking of IgG recycling in vitro and the more potent PD effect in vivo.

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Engineering of human sialidase Neu2 as novel immunotherapy

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Post written by Czeslaw Radziejewski, Ph.D.

Antibody Engineering & Therapeutics, held in December 2022, offered many opportunities to hear exciting and informative presentations by experts in the field, including Li Peng, Ph.D., who discussed “Engineering of human Sialidase Neu2 as Novel Immunotherapy for Degrading Immunosuppressive Sialoglycans to Enhance Antitumor T-Cell Immunity”.

Glycans are the most abundant structures on the cell surface. They are involved in cell communication with immune cells, and abnormal glycans can cause immune dysfunction in cancer and inflammatory diseases. Glycans typically terminate in sialic acid, but in cancer cells, sialic acid is present at a much higher abundance. The most common sialic acid in humans is N-acetylneuraminic acid, which plays a crucial role in numerous intercellular interactions, including with immune cells in the extracellular matrix, epithelial cells, and antibodies. Many studies have shown that sialoglycans are immunosuppressive and that high levels of surface sialoglycans are linked with poor outcomes in many tumor types. Hypersialylation of the surface of cancer cells makes these cells prime ligands for sialic acid-binding immunoglobulin-type lectins (Siglecs), which are found on the surface of immune cells. Once bound to sialylated glycans, Siglecs promote immunosuppressive signaling, thus conferring protection on the tumor cell. There are 15 human Siglecs. In addition, CD-28 is also known to bind sialoglycans. Most immune cells express more than one Siglec.

In her plenary lecture at the 2022 Antibody Engineering & Therapeutics conference, Professor Carolyn Bertozzi, outlined opportunities for the development of cancer treatments based on understanding the cell-surface glycome. She favored degrading sialoglycans with the enzyme sialidase to eliminate the immunosuppression promoted by Siglecs. As proof of concept, a fusion protein was created in Bertozzi’s lab using click chemistry, linking bacterial sialidase to the C-terminus of trastuzumab. The conjugate was tested in a mouse model of a trastuzumab-resistant HER2+ breast cancer model, and the results showed that the treatment essentially abrogated tumor growth. Based on these promising findings, Bertozzi cofounded Palleon Pharmaceuticals to explore sialidase-based biotherapies for cancer treatment.

At the conference, Dr. Li Peng, Chief Scientific Officer of Palleon Pharmaceuticals, presented the company’s progress in moving this concept toward the clinic. Palleon created a set of proprietary Siglec-based reagents for immunohistological hypersialylation detection and probing its role in immunotherapy resistance. Using such reagents, Palleon examined tissues from metastatic melanoma patients treated with PD1 blockade and showed that patients with a high level of sialylation fared much worse than patients with lower levels of sialoglycans. Following Bertozzi’s line of reasoning, the company pursued a strategy of using the enzymatic functionality of sialidase to remove excessive cell-surface sialylation. To translate this idea into a human therapeutic, Palleon decided to use a genetic fusion of sialidase with human Fc.

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