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Call for Papers: Collection on Bispecific and Multispecific Antibodies

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Antibodies and antibody derived bispecifics are one of the most successful therapeutic classes due to their excellent target specificity and tunable drug-like properties. The ability to tailor antibody functions using modern engineering approaches has ushered in a new wave of bi- and multi-specific antibody therapeutics that unlock novel target classes, biology, and mechanisms of action for the treatment of human diseases. In this collection of reviews, we invite The Antibody Society members, mAbs readers, and the broader scientific community to contribute review articles focused on bispecific and multispecific antibody-based molecules. The reviews should narrate the current state of the art in bi- and multi-specific antibody therapeutics, challenges and opportunities, and speculate on new vistas for the field.

mAbs will waive publication charges for up to 8 of the best review articles selected from pre-submission inquiries, which should include the authors, title, abstract, and general outline of the intended review article.

We are particularly interested in reviews in the following topics:

•         Overview of bispecific and multispecific antibody platforms (includes but not limited to Fc engineering, heavy and light chain pairing methodologies, high throughput production methods, geometrical and valency considerations etc.).

•         Reviews on multispecific antibodies (beyond bispecifics i.e., more than two binding epitopes) and their applications.

•         Reviews on bispecifics and multispecific antibodies beyond oncology (i.e., neurology, infectious disease, ophthalmology, rare diseases etc.).

•         Reviews on various cell engagers (T cells, NK cells, macrophages etc.), overview of their design strategies, formats, applications and considerations for safety and tolerability in multiple disease areas.

•         Bispecific/Biparatopic and multispecific/multiparatopic targeting beyond antibodies (Antibody drug conjugates, antibody cytokine fusions, CAR-T/NK/M therapies, ProTACs etc) in various therapeutic areas.

•         Clinical development experience with bispecific and multispecific molecules with a focus on any or all of these areas: safety and tolerability, immunogenicity, biomarkers and/or bioanalytical assay development.

•         Reviews on tissue targeting via bispecific and multispecific antibodies, important considerations for safety, tolerability and preclinical and clinical development.

•         Focused review on developability of bispecific and multispecific molecules, CMC and manufacturing considerations. Bispecifics design and challenges in cell line development, upstream and downstream process development, analytical method development, product quality control strategy, process design and scale up, material demand and commercial manufacturing, regulatory guidance, etc.

Although these topics are especially of interest, we welcome well-written reviews in related areas as well. We intend to waive publication charges for up to 8 of the best review articles selected from pre-submission inquiries, which should consist of the title, abstract and general outline of the intended review article.

The deadline for pre-submission enquiries is January 31, 2023, and the deadline for submission of the completed review articles is August 15, 2023.

Please send pre-submission inquiries to Editor-in-Chief Dr. Janice Reichert (reichert.biotechconsulting@gmail.com), and Assistant Editors Drs. Nimish Gera (ngera@mythictx.com), Li Zhou (li.zhou@abbvie.com) and Jonathan Sockolosky (jonathan@curie.bio). Please feel free to contact us if you have any questions.

For examples of other mAbs Collections, please visit the journal website.

TECVAYLI® (teclistamab) approved in the European Union

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On August 24, 2022, The Janssen Pharmaceutical Companies of Johnson & Johnson announced the first approval worldwide for TECVAYLI® (teclistamab) by the European Commission, which granted conditional marketing authorization (CMA) of TECVAYLI® as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma (RRMM). Patients must have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.

Teclistamab (JNJ-64007957) is an IgG4l T-cell redirecting antibody derived from Ligand’s transgenic mouse (OmniAb) and Genmab’s DuoBody technology. The antibody selectively targets BCMA and CD3. Teclistamab was granted the European Medicines Agency’s PRIME designation for treatment of adult patients with relapsed or refractory MM who previously received ≥3 prior lines of therapy in 2021. Teclistamab had previously been granted Orphan Drug designations for MM in both the US and EU, and FDA granted Breakthrough Therapy designation to teclistamab for the treatment of relapsed or refractory MM.

The CMA was supported by positive results from the multicohort, open-label Phase 1/2 MajesTEC-1 study (NCT03145181 and NCT04557098), evaluating the safety and efficacy of teclistamab in adults with RRMM (n =165). In the MajesTEC-1 study, treatment with teclistamab resulted in deep and durable responses. The median duration of progression-free survival and the median duration of overall survival were 11.3 months (95 percent CI; range, 8.8–17.1) and 18.3 months (95 percent CI; range, 15.1–not estimable), respectively.

Janssen submitted a biologics license application to the US Food and Drug Administration seeking approval of teclistamab for the treatment of patients with relapsed or refractory multiple myeloma in December 2021.

Data for all approved antibody therapeutics can be found here.

Targeting two receptors can significantly increase cell specificity

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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.

Join us on April 7th for our next webinar, Precision Execution of Bispecifics at Scale from Design to Delivery!

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Thursday April 7, 2022 11am ET / 5pm CET
Speaker: Dr. Lisa Prendergast, Associate Director of Expression System Sciences in Licensing at Lonza

Registration for our next webinar, “Precision Execution of Bispecifics at Scale from Design to Delivery“, is now open!

Novel therapeutic modalities such as bispecific antibodies are increasingly being explored as more effective alternatives to monoclonal antibodies for a range of diseases. Therapeutics such as bispecifics, can have a combinatorial effect by targeting two antigens,  resulting in treatments with enhanced utility, higher efficacy, fewer side effects and less resistance compared to mAbs.

Generating a bispecific antibody, which is correctly and stably paired, is a major production concern. Many solutions require significant changes to native antibody structure, which increases antibody complexity and forces adaptation of downstream processes. While a various platforms have been developed to mitigate Heavy-Light chain (HC-LC) mispairing, there are many other rate limiting steps for efficiently expressing these molecules in a CHO system. bYlok® technology is a design engineering approach that stabilise the interaction between the HC and LC, essentially removing the mispairing problem whilst retaining a more natural antibody structure.

This presentation will introduce you to a mechanistic review of the bispecific pipeline to demonstrate how a various tools and technologies can enable you execute bispecifics.  Case studies will be presented to show how the bYlok® technology can be used to stabilise and select for novel bispecifics from a panel of parental immunotherapeutic mAbs. Our data demonstrates that correct heterodimerisation can be achieved consistently and how standard downstream purification processes can be used during production.

Register here!

Clinical-stage ROR1xCD3 bispecific antibodies with potential for broad cancer specificity

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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.