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For World Cancer Day 2024, The Antibody Society has prepared a snapshot of the clinical development of therapeutic antibodies for cancer indication.
The infographic gives an overview on the trends in first in human studies and approvals, as well as on the active early and late stage pipelines (as of January 2024).
In this 15th installment of the annual ‘Antibodies to Watch’ article series, we review commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those granted a first approval in any country in 2023. We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14–32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutic development efforts by the biopharmaceutical industry are robust and increasingly successful.
The complete abstract is here: The ‘Antibodies to Watch’ article series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those recently granted a first approval in any country. In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi)). We briefly review 26 product candidates for which marketing applications are under consideration in at least one country or region, and 23 investigational antibody therapeutics that are forecast to enter regulatory review by the end of 2024 based on company disclosures. These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody–drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa). We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14–32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutic development efforts by the biopharmaceutical industry are robust and increasingly successful.
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.
Antibody Engineering & Therapeutics, held in December 2021, offered many opportunities to hear exciting and informative presentations by experts in the field. We are pleased to present here a summary of a lecture given in the “Immune Cell Recruitment and Redirection” session by Dr. Jonathan Davis. The summary was kindly written by Dr. Czeslaw Radziejewski.
Targeting two receptors can significantly increase cell specificity.
Jonathan Davis, Vice President of Innovation and Strategy, Invenra, Inc.
Jonathan Davis presented a talk detailing Invenra’s rationale for generating bispecific antibodies that target two receptors at the same cell and provided some examples of their biological activity. The platform is based on the construct in which CH1/CL domain in one arm is substituted with a domain derived from CH3. This approach produces stable constructs that are easy to purify. The presentation focused on bispecifics referred to as SNIPERs. The idea behind bispecific SNIPERs is to combine two binding arms, both of which having low affinity toward their cellular targets. When both targets are engaged with cognate targets on the cell surface, the avidity effect results in much stronger binding. This approach could potentially address undesirable binding of monospecific antibodies to healthy tissues where tumor antigen is also expressed at lower levels.
Dr. Davis discussed the concept of symmetric synergy and asymmetric synergy. In the case of symmetric synergy both targets are present at about the same density, whereas in asymmetric synergy one target is present in much greater abundance than the other. According to the speaker, for the symmetric synergy to occur the two target molecules have to be in a right orientation, so the epitopes have to be properly oriented in respect to each other, at least most of the time. This necessitates screening large number of antibodies in order to build a bispecific that demonstrates good synergy. With good geometry fit, 100- to 1000-fold increases in affinity can be reached on cells. He cited the IL-2 receptor system as an example of asymmetric synergy found in nature. High affinity IL-2 receptor is a three-part system consisting of alpha, beta, and gamma subunits. The alpha subunit is present in high concentration, but binds IL-2 with low affinity. The alpha subunit with bound IL-2 binds to beta and then to gamma subunits to form a high affinity signaling complex. This process goes in one direction: from alpha to beta and gamma and that is why it is considered asymmetric. Dr. Davis emphasized that Invenra has the ability to generate and screen large number of constructs to select the right candidate for further development.
Invenra is exploring the SNIPER approach for Treg depletion and for the agonism of co-stimulatory receptor for T cells, OX40. In this lecture, Dr. Davis discussed the anti-tumor activity of SNIPER INV721 in neuroblastoma. The marketed antibody therapeutic, dinutuximab, targets disialoganglioside GD2 that is densely expressed on neuroblastoma cells. GD2 is also expressed on melanomas, small cell lung cancers and sarcomas. Dinutuximab causes lysis of GD2-expressing cells and its mechanism of action involves ADCC and CDC. The antibody is very effective, but causes excruciating pain in patients, presumably because the ganglioside is expressed in all tissues, albeit at the much lower levels. As a second target of INV721, Invenra selected the check-point molecule B7H3 (CD276) that is present only on the tumor cells. To reduce affinity for ganglioside GD2, some residues in the existing antibody against the target were mutated, which allowed the generation of SNIPER( INV721) that bound to neuroblastoma cells only if two targets were present, but not either one alone. To test the in vivo binding affinity of the bispecific antibody, INV721 was radiolabeled with 89Zr. Mice bearing GD2/B7H3-expressing tumors were intravenously injected with 89Zr-labeled INV721 and its in vivo biodistribution was monitored via positron emission tomography imaging. 89Zr-INV721- showed elevated accumulation in the tumor with minimal uptake in normal tissues. 89Zr-radiolabeled isotype control antibody displayed significantly lower tumor uptake demonstrating the specificity of INV721. (1) Dr. Davis indicated that one potential extension of the Invenra bispecific antibodies approach would be to convert these molecules into T-cell engagers.
1. Erbe AK et al. Specific Targeting of Tumors Through Bispecific SNIPER Antibodies. J Immunol, May 1, 2020, 204 (1 Supplement) 91.2.
Antibody Engineering & Therapeutics, held in December 2021, offered many opportunities to hear exciting and informative presentations by experts in the field. We are pleased to present here a summary of a lecture given in the “Immune Cell Recruitment and Redirection” session by Prof. Kerry Chester. The summary was kindly written by Dr. Czeslaw Radziejewski.
Clinical-stage ROR1xCD3 bispecific antibodies with potential for broad cancer specificity.
Kerry Chester, Professor of Molecular Medicine at University College London and CSO of Novalgen.
The leading molecule of Novalgen is NVG-111, a first-in-class tandem T-cell engager in single-chain variable fragment (scFv) format. One arm of NVG-111 targets a T-cell coreceptor, CD3, while the second binds to the tumor-associated tyrosine kinase-like receptor ROR1. ROR1 was cloned in 1992 from a neuroblastoma cell line. (1) The function of ROR1 as a tyrosine kinase is still poorly understood, although some studies show evidence of its intrinsic tyrosine kinase activity. ROR1 is a cell-surface oncofetal antigen, expressed during embryogenesis and largely absent in normal adult organs, with only low-level expression on adipocytes, pancreas, and parathyroid glands. In contrast to the lack of expression in healthy tissues, ROR1 is present in a wide range of cancers and cancer initiating stem cells. It is expressed in both hematological malignancies and in solid tumors. (2)
ROR1 has three extracellular domains: Kringle, Frizzled and Ig-like domain. ROR1 sequences of extracellular domain (ECD) are highly similar between different species. For example, there is 97.6% identity between mouse and human ROR1 ECD. Many years after the initial ROR1 discovery, its ligand was identified as Wnt-5a, one of the Wnt family signaling molecules. Unlike other ROR1 clinical candidates under development, the anti-ROR1 arm of NVG-111 binds to ROR1 Frizzled domain.
Novalgen began the development of NVG-111 by immunizing rats with recombinant extracellular domain of ROR1. The majority of the resulting antibodies bound to Ig-like domain, none bound to Kringle domain, and only one clone (clone F) bound to Frizzled domain. Clone F was selected for further development. Using flow-cytometry, Novalgen demonstrated binding of clone F to a large number of human cancer cell lines. Clone F was humanized and used to format a bispecific scFv with humanized anti-CD3. NVG-111 binds to mouse and to human ROR1 with low nanomolar affinity, but the anti-CD3 arm does not bind to mouse CD3.
In preclinical studies NVG-111 was effective in in-vitro and in an in-vivo mice model of hematological malignancies, and it demonstrated the ability to kill solid tumor in an established PANC-1 mouse xenograft model of human pancreatic carcinoma. NVG-111 also demonstrated killing in models of advanced solid tumors. It eliminated CD44+/CD24- cancer stem cells in a solid tumor model of triple-negative breast cancer. It induced dose-dependent killing in chronic lymphocytic leukemia (CLL) patient samples where patient CLL cells were cocultured with autologous T cells with EC50 in the range of 4-100 pg/ml. NVG-111 showed T cell-mediated killing of mantle cell lymphoma (MCL) cells that was as effective as killing by blinatumomab, which binds CD3 and CD19, but with 2—30% lower levels of cytokine release (measured as interferon gamma) than blinatumomab, suggesting lower risk of cytokine-release syndrome. Toxicity studies performed in mice using AAV expressing NVG-111 showed lack of toxicity at levels 20- to 1000-fold of expected steady-state levels in clinical dose. Because over 90% of CLL/MCL patients are ROR1 positive, the current focus of Novalgen clinical studies are these two hematological malignancies. Importantly, ROR1 is not expressed on normal B cells, therefore risk of B cell aplasia is expected to be reduced.
1. Masiakowski P, Carroll RD. A novel family of cell surface receptors with tyrosine kinase-like domain. J Biol Chem. 1992;267(36):26181-90.
2. Yuming Zhao et al. Tyrosine kinase ROR1 as a target for anti-cancer therapies. Front. Oncol., 11:680834. doi: 10.3389/fonc.2021.680834.
