The Antibody Society

the official website of the antibody society

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

You are here: Home / Archives for antibody therapeutics

First global approval for glofitamab (COLUMVI®)

by

Hoffmann-La Roche Limited (Roche Canada) announced that on March 24, 2023 Health Canada authorized COLUMVI® (glofitamab for injection) for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from follicular lymphoma (trFL), or primary mediastinal B-cell lymphoma (PMBCL), who have received two or more lines of systemic therapy and are ineligible to receive or cannot receive CAR-T cell therapy or have previously received CAR-T cell therapy. COLUMVI has been issued marketing authorization with conditions, pending the results of trials to verify its clinical benefit. The authorization of COLUMVI® is the first in Canada and globally.

Glofitamab (RO7082859) is a full-length IgG1λ/ҡ bispecific T cell redirecting antibody targeting CD20 on malignant B cells and CD3 on T cells. This bispecific antibody was developed by Roche using the 2:1 CrossMab technology, characterized by 3 antigen-binding fragment (Fab) arms enabling monovalent binding to CD3ɛ and bivalent binding to CD20, with the second CD20 arm fused to the CD3ɛ-binding arms via a flexible linker. Glofitamab also features a heterodimeric Fc region engineered with PG LALA mutations to abolish binding to FcɣRs and C1q.

The Health Canada authorization is based on data from the open-label, phase I/II, multicenter, multi-cohort trial (NP30179) conducted to evaluate COLUMVI as monotherapy in patients with relapsed or refractory B-cell lymphoma. In the single-arm DLBCL cohort (n=108), 84.3% of patients were refractory to their most recent therapy and about one-third (34.3%) had received prior CAR T-cell therapy. The primary efficacy outcome measure was complete response (CR) rate as assessed by the IRC using 2014 Lugano response criteria. Results showed that 35.2% of patients (n=38/108) achieved a complete response (CR; a disappearance of all signs of cancer), and 50.0% (n=54/108) achieved an objective response (OR; the combination of CR or partial response, a decrease in the amount of cancer in their body).

An marketing authorization application containing data from the Phase 1/2 NP30179 study (NCT03075696) evaluating glofitamab for NHL was submitted to the European Medicines Agency. A biologics license application for glofitamab undergoing review by the Food and Drug Administration has a first action date of July 1, 2023.

Need data for other antibody therapeutics that have received marketing authorizations? Go to our searchable table of approved antibody therapeutics and those in regulatory review for more information.

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

by

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.

[Read more…]

Engineering of human sialidase Neu2 as novel immunotherapy

by

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.

[Read more…]

Wondering which Antibodies to Watch in 2023?

by

Join us for our next webinar to learn which late-stage antibodies you should watch next year!

Registration is open!

Antibodies to Watch in 2023

 

Thursday January 12, 2023, 11am ET / 4pm CET

Speakers: Drs. Janice Reichert, Silvia Crescioli, Alicia Chenoweth & Jyothsna Visweswaraiah

“Antibodies to Watch in 2023” highlights key events in commercial monoclonal antibody therapeutics development that occurred in 2022 and forecasts events that might occur in 2023. In this presentation, we will discuss the antibody therapeutics granted first approvals in either the United States or European Union in 2022, which include 4 bispecific antibodies ((tebentafusp, faricimab, mosunetuzumab and teclistamab) and 1 ADC (mirvetuximab soravtansine). We will also discuss approvals for antibody therapeutics that were first granted in China or Japan in 2022, which include 2 bispecific antibodies (cadonilimab and ozoralizumab). Globally, at least 24 investigational antibody therapeutics are undergoing review by regulatory agencies. Our data show that, with antibodies for COVID-19 excluded, the late-stage commercial clinical pipeline grew by ~20% in the past year to include nearly 140 investigational antibody therapeutics that were designed using a wide variety of formats and engineering techniques. Of those in late-stage development, marketing application submissions for at least 23 may occur by the end of 2023, of which 5 are bispecific (odronextamab, erfonrilimab, linvoseltamab, zanidatamab, and talquetamab) and 2 are ADCs (datopotamab deruxtecan, and tusamitamab ravtansine).

Everyone who registers will receive 3 reminders before the event, as well as the link to the On Demand version when it is available.

Registration is open!

FDA approves TZIELD™ (teplizumab-mzwv) to delay the onset of Stage 3 type 1 diabetes

by

On November 17, 2022, the US Food and Drug Administration (FDA) approved TZIELD™ (teplizumab-mzwv) to delay the onset of Stage 3 type 1 diabetes (T1D) in adult and pediatric patients aged 8 years and older with Stage 2 T1D. The approval was based in part on a clinical trial in Stage 2 T1D patients in which TZIELD delayed the median onset of Stage 3 T1D by 25 months, or approximately 2 years, compared to placebo.

Teplizumab is a humanized, anti-CD3e IgG1k antibody originally developed at Tolerance Therapeutics, Inc. and the University of California. The antibody Fc region was mutated (L234A; L235A) to reduce effector functions. Teplizumab binds CD3 expressed on mature T cells and may induce expansion and/or regulatory function in T cell subsets. In 2005, teplizumab was licensed to MacroGenics. In 2018, Provention Bio acquired all rights to teplizumab and subsequently continued its development for the prevention and treatment on T1D. The FDA granted teplizumab Orphan Drug designation for the treatment of recent-onset T1D. Teplizumab was also granted FDA’s Breakthrough Therapy designation for the prevention or delay of clinical T1D in at-risk individuals and EMA’s PRIority MEdicines (PRIME) designation for the same indication. As of October 2022, Provention Bio and Sanofi had entered into a co-promotion agreement for teplizumab.

Provention Bio is currently evaluating teplizumab in patients with newly diagnosed insulin-dependent T1D in the global PROTECT (PROvention T1D trial Evaluating C-peptide with Teplizumab) Phase 3 study (NCT03875729). This randomized, double-blind, placebo-controlled, multicenter trial will enroll 300 patients with recent onset T1D who will be randomized 2:1 to either two 12-day cycles of teplizumab (IV) or placebo. The primary efficacy endpoint is C-peptide change. Secondary endpoints include insulin use, HbA1c, hypoglycemic episodes, and safety. The company expects top line data from PROTECT Phase 3 study in 2H 2023.

Interested in more information about approved antibody therapeutics? Explore our searchable table of antibody therapeutic products for details.