An important step in drug development is the assignment of an International Nonproprietary Name (INN) by the World Health Organization (WHO) that provides healthcare professionals with a unique and universally available designated name to identify each pharmaceutical substance. Monoclonal antibody INNs comprise a –mab suffix preceded by a substem indicating the antibody type, e.g., chimeric (-xi-), humanized (-zu-), or human (-u-). The WHO publishes INN definitions that specify how new monoclonal antibody therapeutics are categorized and adapts the definitions to new technologies. However, rapid progress in antibody technologies has blurred the boundaries between existing antibody categories and created a burgeoning array of new antibody formats. Thus, revising the INN system for antibodies is akin to aiming for a rapidly moving target. The WHO recently revised INN definitions for antibodies now to be based on amino acid sequence identity. These new definitions, however, are critically flawed as they are ambiguous and go against decades of scientific literature. A key concern is the imposition of an arbitrary threshold for identity against human germline antibody variable region sequences. This leads to inconsistent classification of somatically mutated human antibodies, humanized antibodies as well as antibodies derived from semi-synthetic/synthetic libraries and transgenic animals. Such sequence-based classification implies clear functional distinction between categories (e.g., immunogenicity). However, there is no scientific evidence to support this. Dialog between the WHO INN Expert Group and key stakeholders is needed to develop a new INN system for antibodies and to avoid confusion and miscommunication between researchers and clinicians prescribing antibodies.
Anti-CD52 therapy has been shown to be effective in the treatment of a number of B cell malignancies, hematopoietic disorders and autoimmune diseases (including rheumatoid arthritis and multiple sclerosis); however the current standard of treatment, the humanized monoclonal antibody alemtuzumab, is associated with the development of anti-drug antibodies in a high proportion of patients. In order to address this problem, we have identified a novel murine anti-CD52 antibody which has been humanize...
Abstract Antibody based therapies are increasingly applied to prevent and treat human disease. While the majority of antibodies currently on the market are chimeric or humanized antibodies from rodents, the focus has now shifted to the isolation and development of fully human antibodies. By retroviral transduction of B cell lymphoma-6 (BCL-6), which prevents terminal differentiation of B cells and, the anti-apoptotic gene B-cell lymphoma-extra large (Bcl-xL) into primary human B cells we efficie...
A total of 111 Ag–Ab x-ray crystal structures of large protein Ag epitopes and paratopes were analyzed to inform the process of eliciting or selecting functional and therapeutic Abs. These analyses illustrate that Ab contact residues (CR) are distributed in three prominent CR regions (CRR) on L and H chains that overlap but do not coincide with Ab CDR. The number of Ag and Ab CRs per structure are overlapping and centered around 18 and 19, respectively. The CR span (CRS), a novel measure introdu...
New broad and potent neutralizing HIV-1 antibodies have recently been described that are largely dependent on the gp120 N332 glycan for Env recognition. Members of the PGT121 family of antibodies, isolated from an African donor, neutralize ∼70% of circulating isolates with a median IC50 less than 0.05 µg ml−1. Here, we show that three family members, PGT121, PGT122 and PGT123, have very similar crystal structures. A long 24-residue HCDR3 divides the antibody binding site into two functional surf...
This report describes the design, generation and testing of Ylanthia, a fully synthetic human Fab antibody library with 1.3E+11 clones. Ylanthia comprises 36 fixed immunoglobulin (Ig) variable heavy (VH)/variable light (VL) chain pairs, which cover a broad range of canonical complementarity-determining region (CDR) structures. The variable Ig heavy and Ig light (VH/VL) chain pairs were selected for biophysical characteristics favorable to manufacturing and development. The selection process incl...
Broadly neutralizing antibodies (bNAbs) to HIV-1 can prevent infection and are therefore of great importance for HIV-1 vaccine design. Notably, bNAbs are highly somatically mutated and generated by a fraction of HIV-1-infected individuals several years after infection. Antibodies typically accumulate mutations in the complementarity determining region (CDR) loops, which usually contact the antigen. The CDR loops are scaffolded by canonical framework regions (FWRs) that are both resistant to and ...
Summary Background A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer. Methods The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients...
Passive transfer of broadly neutralizing HIV antibodies can prevent infection, which suggests that vaccines that elicit such antibodies would be protective. Thus far, however, few broadly neutralizing HIV antibodies that occur naturally have been characterized. To determine whether these antibodies are part of a larger group of related molecules, we cloned 576 new HIV antibodies from four unrelated individuals. All four individuals produced expanded clones of potent broadly neutralizing CD4-bind...
The immunogenicity of protein therapeutics has so far proven to be difficult to predict in patients, with many biologics inducing undesirable immune responses that are directed towards the therapeutic resulting in reduced efficacy, anaphylaxis and occasionally life threatening autoimmunity. The most common effect of administrating an immunogenic protein therapeutic is the development of a high affinity anti-therapeutic antibody response. Furthermore, it is clear from clinical studies that protei...
: Nearly all therapeutic proteins induce antibodies in patients. However this immunogenicity has been neglected in the use of these products, even though the antibodies may have severe consequences. During the last few years, progress has been made in understanding why patients do not tolerate these protein therapeutic products and also how to manage the problem of immunogenicity.
#1Charlotte U. Zajc(BOKU: University of Natural Resources and Life Sciences, Vienna)
#1Charlotte U. Zajc(BOKU: University of Natural Resources and Life Sciences, Vienna)H-Index: 2
Last. Michael W. Traxlmayr(BOKU: University of Natural Resources and Life Sciences, Vienna)H-Index: 13
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T cells that are genetically engineered to express chimeric antigen receptors (CAR T cells) have shown impressive clinical efficacy against B cell malignancies. In contrast to these highly potent CD19-targeting CAR T cells, many of those directed against other tumor entities and antigens currently suffer from several limitations. For example, it has been demonstrated that many scFvs used as antigen binding domains in CARs show some degree of oligomerization, which leads to tonic signaling, T cel...
Last. Arne Skerra(TUM: Technische Universität München)H-Index: 54
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The lack of a non-invasive test for malignant thyroid nodules makes the diagnosis of thyroid cancer (TC) challenging. Human galectin-3 (hGal3) has emerged as a promising target for medical TC imaging and diagnosis because of its exclusive overexpression in malignant thyroid tissues. We previously developed a human-chimeric αhGal3 Fab fragment derived from the rat monoclonal antibody (mAb) M3/38 with optimized clearance characteristics using PASylation technology. Here, we describe the elucidatio...
Few monoclonal antibodies are currently approved for treating infectious diseases, but multiple products are in development against a broad range of infectious diseases, including Ebola, influenza, hepatitis B, HIV, dengue, and COVID-19. The maturity of mAb technologies now allow us to identify and advance neutralizing mAb products to the clinic at "pandemic pace", as the pipeline of mAbs targeting SARS-CoV-2 has demonstrated. Ensuring global access to these products for passive immunization, ho...
Monoclonal antibody therapeutics are often produced from non-human sources (typically murine), and can therefore generate immunogenic responses in humans. Humanization procedures aim to produce antibody therapeutics that do not elicit an immune response and are safe for human use, without impacting efficacy. Humanization is normally carried out in a largely trial-and-error experimental process. We have built machine learning classifiers that can discriminate between human and non-human antibody ...
#1Brian A. Baldo(Kolling Institute of Medical Research)H-Index: 54
#2Nghia H. Pham(Kolling Institute of Medical Research)H-Index: 8
Proteins dominate the extensive and growing list of approved biotherapeutic agents used in medicine today. Proteins, as targeted antibodies, tiny concentrations of hormones and cytokines; many enzymes; fusion proteins and receptors; “factors” involved in blood-clotting, homeostasis, and thrombosis; and vaccines, often in recombinant form, comprise the majority of FDA- and EMA-approved biologics. Of the 51 different mAbs currently approved and many under development for the management of a variet...
#2Artur Burmańczuk(University of Life Sciences in Lublin)H-Index: 5
Last. W. Markiewicz(University of Warmia and Mazury in Olsztyn)H-Index: 10
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Definitions of biological medicinal products (BMPs) vary depending on the source. BMPs are manufactured using complex biological/biotechnological processes involving living cell lines, tissues and organisms such as microorganisms, plants, humans and even animals. Advances in modern biotechnological methods and genetic engineering have made it possible to search for new drugs with a targeted effect and simultaneous reduction of adverse effects, which has resulted in BMPs dynamically increasing th...
Last. Paolo Marcatili(DTU: Technical University of Denmark)H-Index: 22
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Abstract Patent literature should be a reflection of thirty years of engineering efforts in developing monoclonal antibody therapeutics. Such information is potentially valuable for rational antibody design. Patents however are not designed to convey scientific knowledge, but rather legal protection. It is unclear whether antibody information from patent documents, such as antibody sequences could be useful for the therapeutic antibody sphere in conveying engineering know-how rather than act as ...
Last. Jos H. Beijnen(UU: Utrecht University)H-Index: 136
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Therapeutic monoclonal antibodies (mAbs) are rapidly taking over the treatment of many malignancies, and an astonishing number of mAbs is in development. This causes a high demand for quantification of mAbs in biomatrices both for measuring therapeutic mAb concentrations and to support pharmacokinetics and pharmacodynamics studies. Conventionally, ligand-binding assays are used for these purposes, but LC-MS is gaining popularity. Although intact (top-down) and subunit (middle-down) mAb quantific...
#2Justus Weber(Scripps Research Institute)H-Index: 2
Last. Christoph Rader(Scripps Research Institute)H-Index: 57
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Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues, but is up-regulated in a diverse set of hematologic and solid malignancies. Thus, ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we descr...
: Antibodies often undergo substantial engineering en route to the generation of a therapeutic candidate with good developability properties. Characterization of antibody libraries has shown that retaining native-like sequence improves the overall quality of the library. Motivated by recent advances in deep learning, we developed a bi-directional long short-term memory (LSTM) network model to make use of the large amount of available antibody sequence information, and use this model to quantify ...