Two targets, one solution: The rise of bispecific antibodies

Offering a two-in-one approach to delivering targeted therapeutics to patients and providing a versatile solution to the challenges associated with the co-administration of drugs, bispecific antibodies are all the rage at the minute in the biopharma industry. This can be seen in the flurry of approvals for these types of drugs in the last few years – while only three bispecific antibodies had been approved before 2021 throughout the U.S. and the European Union (EU), there are now 12 on the U.S. market alone, with many more likely to receive approval in the coming years.

So, with all of the hype surrounding them, what exactly are bispecific antibodies and what advantages do they hold compared to other classes of drugs?

What are bispecific antibodies?

Bispecific antibodies are basically next-generation monoclonal antibodies (mAbs). But whereas mAbs target just one epitope (a part of an antigen that interacts with immune cells, such as T-cells and B-cells, in the immune system), bispecifics have two distinct binding domains that can bind to two antigens or two epitopes of the same antigen simultaneously.

By targeting two antigens or epitopes, bispecific antibodies can cause multiple physiological or anti-tumor responses, which may be independent or connected. This dual-action approach means that drug developers need to manufacture only one molecule and patients may need only one antibody treatment. This is beneficial because it lessens the patient burden and also overcomes the potential issues surrounding the co-administration of different drugs – an approach becoming more popular in oncology – such as dose-limiting toxicities and drug-drug interactions. Plus, their synergistic features may actually produce more significant treatment effects.

What are the applications of bispecific antibodies?

While bispecific antibodies have the potential to treat a wide range of diseases – such as autoimmune, neurodegenerative, ocular, hematologic, etc. – most are currently in development to treat cancer. They are seen as being particularly useful when it comes to refractory or resistant forms of cancer, which is a growing challenge in oncology that desperately needs addressing.

“Many existing cancer therapies, such as traditional monoclonal antibodies and small-molecule drugs, face limitations that hinder their effectiveness,” explained Jeng Her, chief executive officer (CEO) of bispecific-focused biopharma company AP Biosciences. “These treatments often target a single pathway, which can allow cancer cells to adapt and develop resistance, diminishing the drug’s long-term efficacy.”

Her continued to explain that because the design of bispecific antibodies allows for conditional activation, it minimizes on-target off-tumor activity, allowing drug developers to focus their activity in the tumor microenvironment, where it is needed the most. “Furthermore, by allowing for multiple functional domains on the antibody products, bsAbs [bispecific antibodies] can not only bind tumor antigens but can, for example…simultaneously engage tumor immune cell receptors and significantly enhance the immune response against cancer cells, reducing the likelihood of resistance development,” he added.

Approved bispecific antibodies: The current landscape

Technically speaking, the first bispecific antibody to gain regulatory approval was called catumaxomab after receiving the nod from the European Medicines Agency (EMA) in 2009 for the treatment of patients with malignant ascites. However, it was voluntarily withdrawn from the market in 2017 due to commercial reasons. It was followed by Amgen’s blinatumomab, which became the first bispecific to receive U.S. Food and Drug Administration (FDA) approval for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in 2014. Since then, many more approvals have followed for the treatment of a variety of conditions.

According to Her, the bispecific antibody landscape is rapidly evolving, with 12 bispecific antibodies currently approved by the FDA, and four more in regulatory review for approval this year. “These approvals primarily target cancer, hematologic conditions, and ocular diseases,” he said.

Her added that, along with blinatumomab, some of the most significant bispecific antibodies that have been approved include Hemlibra (emicizumab) for hemophilia A, and Rybrevant (amivantamab) for non-small cell lung cancer. Meanwhile, the most recent approval was for Amgen’s tarlatamab – greenlit by the FDA in May – to treat extensive stage small cell lung cancer.

Bispecific antibodies in clinical trials

There are currently more than 100 bispecific antibodies in clinical development, most of which are still in the early stages. Some of the biggest names in biotech and pharma are at the forefront of development in the field, including the likes of Amgen, Regeneron, Genentech, Janssen, and Pfizer.

In fact, Regeneron made headlines just recently regarding its relapsed or refractory multiple myeloma bispecific candidate, linvoseltamab, after the FDA rejected its filing for approval for the candidate, issuing a complete response letter due to third-party manufacturing concerns – an issue that is all too familiar for Regeneron. However, if the candidate is eventually approved, Regeneron could challenge Johnson & Johnson (J&J) and Pfizer in the blood cancer market. At 71%, the overall response rate for linvoseltamab in its phase 1/2 trial makes it higher than the results for J&J’s Tecvayli and Pfizer’s Elrexfio, and its complete response rate is also competitive at 46%. Additionally, Regeneron has identified the rate of cytokine release syndrome, and the speed at which the adverse event emerges, as a point of differentiation that could favor linvoseltamab.

Another bispecific antibody that recently made headlines is Akeso and Summit Therapeutics’ ivonescimab, which combines the power of immunotherapy via a blockade of PD-1 with the anti-angiogenesis benefits of an anti-VEGF – two targets critical for tumor growth and survival – into a single molecule. Data from a phase 3 study showed that the bispecific slashed the risk of disease progression or death by an incredible 49% compared with Merck’s Keytruda in patients with previously untreated, PD-L1-positive non-small cell lung cancer (NSCLC). This means that, if approved, ivonescimab has the potential to become a new standard of care treatment for NSCLC.

Meanwhile, Her’s own company, AP Biosciences, is also advancing multiple bispecific antibody candidates through the clinic. The company’s lead candidate is AP505, which also targets PD-L1 and VEGF. “By blocking PD-L1, AP505 removes the brakes from the immune system, allowing T cells to attack cancer cells more effectively,” explained Her. “Meanwhile, targeting VEGF, disrupts the blood supply to tumors, starving it of the nutrients it needs to grow.” This candidate is currently in a phase 1 trial in China for solid tumors, with preliminary data expected by the end of this year.

AP Bioscience’s second clinical candidate is called AP203, which is designed to bind PD-L1 while also engaging CD137. Her explained that by targeting PD-L1, AP203 prevents T cell suppression and enhances immune system detection of cancer cells. Meanwhile, activation of CD137 promotes T cell proliferation and survival, leading to a more robust and sustained anti-tumor response.

“However, what sets AP203 apart is its unique ability to activate T cells conditionally – only when both targets are present – thereby focusing its effects within the tumor microenvironment,” continued Her. “This approach, enabled by our T-CUBE platform, not only amplifies the immune response but also minimizes the risk of systemic toxicity, such as the cytokine release syndrome, offering a potentially safer and more efficacious option for patients.”

As well as the already established companies developing bispecific antibodies, the field is continually attracting interest from startups. Just this month, two bispecific antibody companies have launched with impressive funding rounds.

Candid Therapeutics launched with $370 million in series A financing and, in an unusual move for a company just launching, acquired two biotechs – Vignette Bio and TRC 2004 – along with their lead assets. The company aims to develop T cell engagers, which are bispecific antibodies that bind to T cells and a molecule on a target cell, coercing the T cells to attack the target.

Meanwhile, Duke University spinout Adaptin Bio also launched with plans to bring a T cell engager for glioblastoma to the clinic, hoping to prevail where Roche and Amgen did not, as both companies stopped work on their glioblastoma bispecific assets. Adaptin Bio has already received FDA clearance to start a clinical trial for its candidate, which will be run at Duke University and enroll around 25 patients.

Given the number of candidates entering clinical trials, it is likely that we will see an even bigger flurry of bispecific antibody approvals in the coming years.

A flourishing field: Bispecific antibodies market set to see rapid growth

Her believes that we are entering “the era of ‘Antibodies 2.0’, as these modalities become integrated components of multitudinous treatment paradigms and approaches, as monotherapies, antibody-drug conjugates (ADCs), and as combinations with other approaches.”

He said that part of the reason for this belief is because of the sudden increase in popularity of bispecific antibodies, driven by both advancements in antibody engineering and a deeper understanding of cancer biology. “Our ability to design and manufacture these sophisticated molecules has significantly improved, allowing us to target disease mechanisms more precisely and clear the threshold for entry into the clinic.”

In fact, even the FDA has said that, in the future, it anticipates there will be a spectrum of bispecific antibodies developed to prevent, treat, or diagnose diseases, and the agency has been encouraging drug development in this area. In 2021, it finalized guidance on bispecific antibody development programs, which discusses aspects of chemistry, manufacturing, and controls (CMCs) as well as nonclinical and clinical development programs. It also describes the challenges, such as immunogenicity (or causing an immune response) related to the novel structures. In addition, the guidance recommends types of data to support BsAb approvals.

So, it comes as no surprise that the bispecific antibodies market is set to see rapid growth. According to Grand View Research, the global bispecific antibodies market size was valued at $5.73 billion in 2022, and is expected to grow at a compound annual growth rate (CAGR) of 44% from 2023 to 2030. Grand View Research cites rising incidences of chronic diseases such as cancer, autoimmune disorders, and infectious diseases, rising demand for targeted therapies, as well as advancements in antibody engineering technologies, as being some of the major driving factors for this expected growth.

“Bispecific antibodies are more than just a technological advancement; they represent a new, potentially transformative paradigm that extends far beyond oncology,” stressed Her, adding that these dual-action drugs are already being incorporated into multiple therapeutic approaches from ADCs to cell therapies, and this is a trend that is only going to continue.