The Antibody Society’s Post

In regulatory affairs news, Regeneron Pharmaceuticals, Inc. announced that the European Commission has approved Ordspono™ (odronextamab) to treat adult patients with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma, after two or more lines of systemic therapy. This marks the first regulatory approval of Ordspono in the world for these patients. Ordspono is a bispecific antibody that acts by linking the lymphoma cell to a killer T cell. #mabs https://lnkd.in/e_MsYsNR

From the abstract: current genetic study using APP deficiency to remove Aβ completely in various Psen mutant mice provides compelling experimental evidence for the lack of a causal role of Aβ in the age-dependent neurodegeneration and elevated apoptotic cell death in the cerebral cortex caused by Psen mutations. These findings suggest that removal of Aβ is unlikely to be effective for treating familial AD patients carrying PSEN mutations. https://lnkd.in/ex74WuSu

For those involved in regulatory affairs, see item below... For others, first a brief explanation, courtesy of the R Consortium: To bring an experimental clinical product to market, electronic submission of data, computer programs, and relevant documentation is required by health authority agencies from different countries. In the past, submissions have been mainly based on the SAS language. In recent years, the use of open source languages, especially the R language, has become very popular in the pharmaceutical industry and research institutions. Although the health authorities accept submissions based on open source programming languages, sponsors may be hesitant to conduct submissions using open source languages due to a lack of working examples.

A new paper by NIH authors challenges AlphaFold's predictive power and finds it lacking...  From the abstract: Here, we test the limits of its predictive power on fold-switching proteins, which assume two structures with regions of distinct secondary and/or tertiary structure. We find that (1) AF is a weak predictor of fold switching and (2) some of its successes result from memorization of training-set structures rather than learned protein energetics. Combining >280,000 models from several implementations of AF2 and AF3, a 35% success rate was achieved for fold switchers likely in AF’s training sets. AF2’s confidence metrics selected against models consistent with experimentally determined fold-switching structures and failed to discriminate between low and high energy conformations. Further, AF captured only one out of seven experimentally confirmed fold switchers outside of its training sets despite extensive sampling of an additional ~280,000 models. Several observations indicate that AF2 has memorized structural information during training, and AF3 misassigns coevolutionary restraints. These limitations constrain the scope of successful predictions, highlighting the need for physically based methods that readily predict multiple protein conformations. #mabs https://lnkd.in/e9x9-sFN

In a review newly published in mAbs, Integral Molecular authors discuss emerging cell-based protein arrays designed to evaluate mAb specificity. From the abstract: Specificity profiling is a requirement for monoclonal antibodies (mAbs) and antibody-directed biotherapeutics such as CAR-T cells prior to initiating human trials. However, traditional approaches to assess the specificity of mAbs, primarily tissue cross-reactivity studies, have been unreliable, leading to off-target binding going undetected. Here, we review the emergence of cell-based protein arrays as an alternative and improved assessment of mAb specificity. Cell-based protein arrays assess binding across the full human membrane proteome, ~6,000 membrane proteins each individually expressed in their native structural configuration within live or unfixed cells. Our own profiling indicates a surprisingly high off-target rate across the industry, with 33% of lead candidates displaying off-target binding. Moreover, about 20% of therapeutic mAbs in clinical development and currently on the market display off-target binding. Case studies and off-target rates at different phases of biotherapeutic drug approval suggest that off-target binding is likely a major cause of adverse events and drug attrition. #mabs https://lnkd.in/eX9GsfGf

In a new paper, Philogen S.p.A.- and Philochem AG-based authors describe a new multispecific immunocytokine. From the abstract: In this study, we describe Tripokin, a novel multi-specific fusion protein that combines interleukin-2 and a single amino acid mutant of tumor necrosis factor. The two pro-inflammatory payloads were fused to the L19 antibody, a clinical-grade antibody against the extradomain B of fibronectin. The human payloads were used for clinical applications, while the corresponding murine cytokines were used for preclinical studies. The resulting fusion proteins were produced in mammalian cells and purified to homogeneity. The murine Tripokin product was well tolerated in tumor-bearing mice at three doses of 30 μg in a 2-day interval and promoted rapid tumor eradication in murine models, more efficiently than single-agent immunocytokines. Tripokin induced rapid tumor necrosis and stimulated a robust immune response, impacting innate and adaptive immune pathways. In addition, the combination with immune checkpoint inhibitors further boosted the therapeutic efficacy of our molecule. Tripokin represents a promising clinical candidate for the simultaneous delivery of interleukin-2 and tumor necrosis factor to neoplastic sites. https://lnkd.in/eSNVjqYJ

Congratulations to Invenra Inc.! The company announced that its innovative bispecific antibody, INV724, developed for the treatment of neuroblastoma, has been awarded both Rare Pediatric Disease and Orphan Drug Designations by the U.S. Food and Drug Administration. INV724, a product of Invenra’s proprietary B-Body® Bispecific Platform, was developed in collaboration with the University of Wisconsin Carbone Cancer Center. The antibody simultaneously targets GD2 and B7-H3 tumor antigens, demonstrating exceptional specificity for neuroblastoma. Designed to mitigate the severe pain associated with GD2-targeted therapies, INV724 has shown promising preclinical results, including strong therapeutic potential and robust developability. #mabs https://lnkd.in/g_Er7nbe

In more business news, Zenas BioPharma has filed for a US IPO. The company's lead product candidate is obexelimab, a bifunctional monoclonal antibody designed to bind both CD19 and FcγRIIb to inhibit the activity of B cells, plasmablasts, and CD19-expressing plasma cells. The obexelimab clinical programs include an ongoing Phase 3 registration-directed trial in IgG4-Related Disease, two planned Phase 2 randomized controlled trials in multiple sclerosis and systemic lupus erythematosus, and an ongoing open label Phase 2 trial in warm autoimmune hemolytic anemia.  #mabs https://lnkd.in/edB827ft

In business news, Bicara Therapeutics, a clinical-stage biopharmaceutical company involved in the development of treatments for solid tumors, has filed for an initial public offering. The company's lead program ficerafusp alfa is a bifunctional antibody that combines two clinically validated targets, an epidermal growth factor receptor-directed monoclonal antibody with a domain that binds to human transforming growth factor beta. Bicara intends to initiate a pivotal Phase 2/3 trial of ficerafusp alfa in combination with pembrolizumab as a first-line therapy in recurrent/metastatic HNSCC excluding patients associated with human papillomavirus infection (HPV-positive patients) with oropharyngeal squamous cell carcinoma, late in the fourth quarter of 2024 or early in the first quarter of 2025. The Form S-1 registration statement is here: https://lnkd.in/e9Xk5ktU https://lnkd.in/eXDGbT-k

In business news, Oblique Therapeutics AB (publ.) announced that they have entered into a research collaboration agreement with Eli Lilly and Company to apply the AbiProt® technology to generate antibodies to a high-value target. This partnership aims to accelerate research and development into innovative treatments and, if successful, will generate milestones and royalties. Under this collaboration agreement, Oblique will partner with Lilly Catalyze360-ExploR&D, a pillar of external innovation at Lilly that brings enterprise learning, scientific know-how, and best-in-class research and development capabilities to accelerate partner science. The parties already have an existing agreement in place (signed in November 2023) and this agreement expands the collaboration between the companies to a second high-value target. #mabs https://lnkd.in/eq9WvCDW