From Concept to Clinic: Are We Making the Right First Moves in Bispecific Development?

Bispecific antibodies are rapidly becoming one of the most promising modalities in therapeutic development, offering the ability to bind two targets simultaneously and unlock mechanisms that go beyond what traditional monoclonal antibodies can achieve.

The global bispecific antibodies market is projected to grow from $5.7 billion in 2022 to $110 billion by 2030, driven largely by innovation in oncology and autoimmune disease applications.

In cancer — which accounted for over 70% of the bispecifics market in 2022 — these therapies typically act through engaging  tumor-associated antigens and immune cells with precision, aiming to boost efficacy while minimizing off-target toxicity. Inflammatory conditions like rheumatoid arthritis and Crohn’s disease are also areas of growing interest, as bispecifics offer the potential to modulate multiple immune pathways for improved disease control.

While these capabilities unlock new possibilities in oncology, immune modulation and rare disease, they also introduce development challenges — from molecular design and manufacturability to format selection and screening.

In this Xtalks Spotlight interview, we spoke with two experts from Abzena, Arron Hearn, Director and Group Head of Protein Engineering, and Thomas Cornell, Senior Manager of Protein Engineering, about how their team supports early bispecific design decisions.

Together, they shared insights on format selection, manufacturability, clinical progress and strategies to manage risk in a field that is evolving rapidly.

Rethinking Mechanisms of Action

An increasing number of researchers are looking into bispecifics today than ever before, began Hearn.

He pointed to two bispecific monoclonal antibodies already in clinical use: Hemlibra (emicizumab-kxwh; Roche/Chugai), an IgG4-based antibody that brings together two clotting factors in hemophilia A, and Blincyto (blinatumomab; Amgen), a BiTE format that engages T-cells to target and kill cancer cells in hematologic malignancies.

Unlike traditional monoclonal antibodies (mAbs), bispecifics enable the targeting of two epitopes — either on the same protein, two separate proteins or even on two different cell types. These features enable researchers to explore mechanisms that were previously inaccessible.

“It really opens up the possibilities to look at other mechanisms of action that are limited by traditional specific antibodies,” Hearn said.

These applications, he explained, illustrate why bispecifics are being pursued for both unmet needs and novel treatment combinations across a growing range of indications.

Format Selection at the Start of a Bispecific Program

Cornell explained that Abzena doesn’t focus on a single platform but works with whatever format best fits the customer’s scientific and strategic goals.

“Customers tend to come with two main requirements. One is either to have IgG-like bispecific molecules that would maintain the traditional shape and size of an IgG antibody, or people who are more willing to explore different shapes and sizes as well,” said Cornell.

IgG-like formats often rely on established, IP-covered technologies like Fab-arm exchange, CrossMAbs or DuoBodies — engineered solutions that help combine two different antibody arms while avoiding common issues like light chain mispairing, allowing developers to preserve the structure and behavior of a traditional IgG.

In contrast, non-IgG-like designs may use asymmetrical or compact formats such as single-chain Fvs or VHH domains. These can reduce mispairing and support smaller constructs, but they may also add complexity in manufacturing and stability.

He added that the team’s role often involves supporting early decisions around trade-offs between IP access, functional performance and manufacturability.

Structural Lessons from Bispecifics Already in the Clinic

Echoing Cornell’s outlook on format selection, Hearn shifted the focus to bispecifics that have already progressed into the clinic — highlighting which structural strategies have led to regulatory approvals and how developers have addressed pairing and manufacturability challenges in real-world programs.

“If you look at the clinical landscape at the moment, only 17 bispecifics have been approved as of December 2024. Now most of those are kind of focused on very traditional IgG-like molecules — so they do look like antibodies in general.”

He explained that these approved therapies are often built using DuoBody technologies that allow controlled Fab-arm exchange, sometimes in combination with CrossMAb formats or common light chains, to overcome light chain mispairing.

Hearn also noted that newer candidates in the clinic are exploring single-chain molecules. These smaller constructs fuse multiple proteins into one continuous chain, allowing expression and purification without the complexity of co-expressing multiple proteins in a single cell.

“Bispecifics are really growing, so they’re kind of becoming much more popular in terms of the overall concept that people are exploring.”

While technical challenges persist, Hearn pointed to oncology as the most active area in bispecific development, with hundreds of candidates now in preclinical or clinical stages. As the field matures, he expects bispecifics to play an increasingly central role in the therapeutic antibody landscape.

Expanding to Multispecifics and Functional Fusions

When asked about the future beyond bispecifics, Hearn acknowledged that multispecific antibodies — those binding three or more targets — are beginning to enter clinical trials, though none have been approved yet. Their development brings added complexity in both manufacturing and safety, requiring careful consideration of each additional binding domain.

As molecule designs become more ambitious, the challenges compound. Multispecifics not only require advanced production and characterization strategies but also introduce heightened safety concerns due to the increased number of functional domains.

Hearn also pointed to the enhancement of bispecifics themselves. Researchers are combining bispecifics with additional payloads — for example, attaching cytotoxic agents to create Antibody-drug conjugates (ADCs), or conjugating oligonucleotides (AOCs) to enable gene silencing within targeted cells.

These developments reflect how bispecifics are increasingly being adapted or extended in ways that approach multispecific functionality. While these innovations are promising, they increase the complexity of analytical characterization, production scale-up and safety profiling.

“So, there are many, many different ways of adapting a bispecific or generating multispecifics as well,” concluded Hearn.

Designing with Risk — and Flexibility — in Mind

Cornell closed the discussion with practical guidance for teams starting out in bispecific development. He advised against assuming that prior antibody experience will directly translate into success with bispecifics.

“You cannot simply take the biophysics of the previous antibodies and dictate directly how well or badly a bispecific might perform.”

He highlighted risks such as aggregation, affinity loss in single-chain formats and poor expression yields as common pitfalls. The key, he said, is to start with a broad panel of designs rather than placing all bets on a single construct.

“There’s not really a one-size-fits-all approach for a bispecific,” said Cornell. “Trying different technologies — whether IP-covered or not — can give you a broader base to find the right design.”

A strong screening process is equally important. Early binding and functional data help narrow the field quickly, guiding resources toward candidates with the best biological activity and drug-like properties.

Cornell surmised our interview, noting that while the path isn’t straightforward, many of these challenges can be mitigated through careful design and testing.

This article was created in collaboration with the sponsoring company and the Xtalks editorial team.