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First global approval for glofitamab (COLUMVI®)

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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.

FDA approves Zynyz™ (retifanlimab-dlwr) for Merkel cell carcinoma

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On March 22, 2023, the US Food and Drug Administration approved Zynyz™ (retifanlimab-dlwr) for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). Retifanlimab (INCMGA00012, MGA012) is a humanized, hinge-stabilized IgG4k antibody targeting PD-1. The biologics license application for Zynyz for MCC was approved under accelerated approval based on tumor response rate and duration of response.

FDA’s approval was based on data from the Phase 2 POD1UM-201 trial (NCT03599713), an open-label, multiregional, single-arm study that evaluated Zynyz in adults with metastatic or recurrent locally advanced MCC who had not received prior systemic therapy for their advanced disease. In this study, patients received Zynyz 500 mg intravenously every four weeks until disease progression, unacceptable toxicity, for up to 24 months. The primary endpoint was objective response rate (ORR) as determined by independent central radiographic review using RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Among chemotherapy-naïve patients (n=65), Zynyz monotherapy resulted in an ORR of 52% (95% confidence interval [CI]: 40-65). Complete response was seen in 12 patients (18%), and 22 patients (34%) showed partial response. Among the responding patients, the DOR ranged from 1.1 to 24.9+ months; 76% (26/34) experienced a DOR of six months or longer and 62% (21/34) experienced a DOR of 12 months or longer by landmark analysis.

Incyte Corporation, which licensed retifanlimab from MacroGenics in 2017, is sponsoring clinical studies evaluating retifanlimab monotherapy as a treatment for other cancers, including endometrial cancer, non-small cell lung cancer, and squamous cell carcinoma of the anal canal.

Ultralong CDR H3-based knobs: the smallest antibody fragment

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Photo from Adam Morse.

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 Vaughn Smider, Ph.D., President, Applied Biomedical Science Institute, who discussed ultralong CDR H3-based knobs as the smallest antibody fragment and Jeff Allen, Ph.D. Vice President, Protein Sciences, Pelican Expression Technology, who discussed Large-scale production of knob peptides.

In 1997 Osvaldo Lopez and his colleagues [1] at the University of Nebraska analyzed transcripts encoding the variable regions of immunoglobulin heavy chains from adult and fetal bovine splenocytes. They were the first to notice the presence of long heavy chain CDR3s. The bovine CDR3s ranged in length from 13 to 28 amino acids, with the average length of CDR H3 being 21 residues in both adults and fetuses. This was longer than had been previously reported for other mammals. In a subset of bovine antibodies, CDR H3s are ultralong (50-70 AA).[2] The structure of ultralong CDR H3s was solved by Wang et al. [2] and the results demonstrated that ultralong CDR H3s all adopt similar architectures, with each composed of a long protruding beta-ribbon “stalk” and diverse disulfide-bonded “knob” (PDB: 4K3D). Up to six cysteine residues can be found in sequences of bovine CDR H3, all involved in disulfide bridges. The loops within the knob domain are thought to be involved in antigen binding. This contrasts with human antibodies where the antigen binding surface is formed from six CDR loops. Bovine CDR H3s are enormously diverse, and the diversity is generated by somatic hypermutation. [3] There is little diversity in CDR H1 and CDR H2, and cows use one light chain. Cows are not unique in having antibodies characterized by long CDR H3s. Other animals with these antibodies include zebu, yak, American and European bison.

It was previously observed that some broadly neutralizing antibodies against HIV also have longer CDR3s. Sok et al. [4] showed that immunization in cows could elicit rapid generation of neutralizing anti-HIV antibodies. Using x-ray crystallography, cryo-electron microscopy, and site-directed mutagenesis, Stanfield et al. [5] elucidated the structure of one monoclonal antibody elicited in cows by immunization with the HIV envelope trimer and showed molecular details of the knob mini-domain binding to a cryptic site on the gp120 CD4 receptor.

Knob domains are reasonably similar in size and shape to cyclotides/knottins, such as prototypic Cyclotide Kalata B1 and other disulfide-bonded peptides. Clinical applications for T cell immunotherapies are now emerging for analogs of cyclotides, for example, inhibition of the Kv1.3 channel. The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune responses. Sea anemone ShK cyclotide peptide was grafted into the β-ribbon ‘stalk’ of the ultralong CDR H3 scaffold of a humanized bovine IgG and showed the ability to block the Kv1.3. [6] The analog of the ShK peptide called ShK-186 or dalazatide blocks this channel, suppresses T-cell activation and is in human trials as a therapeutic for autoimmune disease.

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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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