Perspectives

Media Insights: Dr. Jijie Gu, CSO of WuXi Biologics, Comments on BsAbs R&D Trend

Jul. 06, 2022

Media Insights: Dr. Jijie Gu, CSO of WuXi Biologics, Comments on BsAbs R&D Trend

Bispecific antibodies (BsAb) has become a trending field in innovative drug development industry. According to WuXi Biologics’ article, Biology Drives the Discovery of Bispecific Antibodies as Innovative Therapeutics, published on industry journal, Antibody Therapeutics, as of September 2019, over 110 bsAbs are under active clinical development, and near 180 in preclinical development.

What makes drug developers fascinated by bispecific antibodies? What are the advantages compared with monoclonal antibodies? In a recent interview with Bio Pharm International, Dr. Jijie Gu, CSO & EVP of WuXi Biologics shared his cutting-edge insights. The article was published in the June issue of the journal.

Questions

1) What has led drug developers to focus on the development of bispecific antibodies?

Most human diseases are complex, often driven by multiple redundant or distinct mechanisms; thereby single-target approach such as mAb may not be sufficient to achieve optimal therapeutic efficacy. Especially, many therapeutic concepts need physical linkage of two or more targets. In this case, bispecific antibodies (bsAbs) or multi-specific antibodies (msAbs) targeting two or more targets may offer novel therapeutic applications that are difficult or impossible to achieve by mAbs.

2) What are bispecific antibodies, and are they an improvement over conventional mAbs?

A bispecific antibody (bsAb) is able to bind two different targets or two distinct epitopes on the same target. Broadly speaking, bsAbs can include any single molecule entity containing dual specificities with at least one being antigen-binding antibody domain. Besides additive effect or synergistic effect, the most fascinating applications of bsAbs are to enable novel and often therapeutically important concepts otherwise impossible by using monoclonal antibodies alone or their combination. This so-called obligate bsAbs could open up completely new avenue for developing novel therapeutics.

3) Mechanistically, how do bispecific antibodies demonstrate a therapeutic effect versus mAbs?

Till Jan. 2022, FDA has approved 5 bsAbs, among which 4 are obligate bsAbs and their mechanism of actions can’t be achieved by simply using mAbs along or their combination. For an example, the newly approved amivantamab targeting both cMET and EGFR showed significant therapeutic benefits in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) carrying EGFR exon 20 insertion mutations. This type of NSCLC is resistant to common EGFR inhibitor therapies. Though combine with EGFRi therapy, EGFR mAb showed some clinical benefit in patients with this type of NSCLC, the associated severe toxicity may limit its application. According to the data published by Jassen, by carefully select and design the cMET and EGFR target arms, amivantamab not only showed promising therapeutic efficacy but also demonstrated improved safety profile, which led to its accelerated approval in 2021.

4) What are the main categories, or areas, of disease that bispecific antibodies are best fit for? In other words, where would bispecific antibodies have a therapeutic impact, potentially where a conventional mAb may be lacking or has failed to have a therapeutic impact?

Among the 5 launched bsAbs, 3 are for cancer treatment, 1 for hemophilia A and 1 for age-related macular degeneration. The bsAb clinical development pipeline is composed predominantly by programs for cancer treatment. Autoimmune disease is the second largest area for bsAbs’ applications. The reasons that majority of the programs are focusing on cancer treatment not only because of the huge unmet medical needs, but a unique class of bsAbs can redirect the immune effector cells to eliminate tumor cells specifically, which is upon the engagement of both of the arms of the bsAb onto the effector cell and tumor cell, respectively. The first FDA approved bsAb, Blincyto, belongs to this category, which redirects T cells to kill tumor cells. Now, with the deep understanding of how immune cells to kill tumor cells, a new wave of many immune cell engager bsAbs with improved clinical efficacy and better safety profile is in the clinical development.

BsAbs and msAbs open up tremendous opportunities to explore previously unexplored therapeutic options. We believe that the next decade will witness the clinical success of bsAbs or msAbs employing some novel MOAs in the applications in cancer and infectious, metabolic, ocular, and other diseases with significant unmet medical needs.

5) What have been the major challenges in bringing bispecific antibody candidates from the research phase to clinical development?

Compared to mAbs, bsAbs display significant complexity in the research and development stages. Technical challenges, especially CMC development challenges, and mechanistic or biology challenges are the major challenges. To tackle technical challenges, many companies are developing various bsAb technologies. We established the WuXiBody^® and SDArBody^TM platforms to enable our partners to develop novel bispecific antibodies. WuXiBody^® exhibits great compatibility to assemble almost any mAb sequence pairs, unique structural flexibility to build multi-valent formats, and excellent developability to pass CMC challenges. Currently two WuXiBody^® molecules are in clinical development and one is in IND filing stage. SDArBody^TM, a single domain antibody based multispecific antibody platform, allows flexibility to build multispecific or multi-functional antibodies to enable unique MOAs for therapeutic applications, and exhibits excellent CMC developability. As a CRDMO company, we had privilege to have worked with many of our clients not only on our proprietary bsAb technologies, but also many other variety of generic bsAb formats, which helped us to accumulate tremendous experience in stable manufacturing cell line generation, protein expression, purification, characterization, and formulation of bsAbs drug substance and drug products to allow them successfully entering clinical development.

In addition to CMC challenges, special testing systems are needed to characterize the potential therapeutic efficacy, toxicity, PK/PD profiles and immunogenicity risk of the bsAb therapeutic candidates at research stage as well as at the preclinical and clinical development stage, and many of these systems may be quite complicated, as compared to the systems used to evaluate mAbs.

More to Read

Besides, Dr. Gu and the WuXi Biologics team shared more insights in the article mentioned above. The article is the first one to classify antibodies in the preclinical and clinical stages, and to present undergoing bsAb projects progress. It introduces a system that classifies bsAb formats into 30 categories based on their antigen-binding domains and the presence or absence of Fc domain. The authors further review the biology applications of approximately 290 bsAbs currently in preclinical and clinical development, with the attempt to illustrate the principle of selecting a bispecific format to meet biology needs and selecting a bispecific molecule as a clinical development candidate by 6 critical criteria. Given the novel mechanisms of many bsAbs, the potential unknown safety risk and risk/benefit should be evaluated carefully during preclinical and clinical development stages. Nevertheless, the authors are optimistic that next decade will witness clinical success of bsAbs or multispecific antibodies employing some novel mechanisms of action and deliver the promise as next wave of antibody-based therapeutics.

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