Are higher-order multispecific antibodies too ambitious?

You’ve probably heard a bit about antibodies.

Whether your knowledge comes from school, those COVID-19 tests we all still have lying around the house, or even from vaccines, you’ll have an idea of their importance in the immune system. We have a lot to thank them for, from binding to specific antigens present on harmful cells and causing agglutination (clumping), to blocking antigens from reaching healthy cells. But traditional antibodies are almost exclusively one-trick ponies: they each bind to a specific epitope (part of an antigen), which is complementary (not to be confused with complimentary!) However, what if antibodies could bind to multiple, different types of antigens? That’s what multispecific antibodies are engineered for – if you didn’t already guess by their name.

Conventional monoclonal antibody treatments have been available for decades, and are one of the biggest pioneering technologies in medicine. Designed in the lab to mimic the function of natural antibodies, they execute targeting, signalling, and blocking. They definitely shouldn’t be overlooked, but it’s not surprising that recently the spotlight has been stolen by their multitasking successors. The ability of multispecific antibodies to bind to multiple different types of antigens allows the targeting of several disease pathways or bridging differing cell types. Unlocking synergised effects, this expands the horizons of drug development for complex disorders. Attention has particularly been drawn to the bispecific T-cell engager subclass to focus on targeting cancer cells. These form a bridge between a T-cell and a cancerous cell, allowing redirection towards tumours. 

There are more flavours of bispecifics than Ben and Jerry’s ice cream

 Paul Carter, Genentech fellow

The antibodies are manufactured using recombinant DNA technology – methods using joined DNA from different origins. A traditional, ‘Y’-shaped monoclonal antibody consists of four chains: two identical light chains and two identical heavy chains. However, IgG-like (with the traditional ‘Y’ shape) formats of multispecific antibodies, which are among the most commonly used, can contain two different light and heavy chains, creating two unique pair combinations. The huge variety of these engineered antibodies continues to grow, and, according to Paul Carter, a fellow at Genentech, “There are more flavours of bispecifics than Ben and Jerry’s ice cream.” Unfortunately, this can create some mishaps in the manufacturing process, such as mispairing (the probability of which understandably increases with the number of potential chain combinations). But these aren’t the only types that are suffering from setbacks, as fragment-shaped antibodies face the challenge of clearing faster from the circulation. While bispecific antibodies are being introduced into treatments (such as for multiple myeloma), trispecific and tetraspecific antibodies are still trailing behind in early clinical trial phases, with more hurdles to overcome.

Unsurprisingly, familiar faces in the pharmaceutical industry are heavily backing this technology, many already having bispecific antibody treatments available on the market. For example, in 2025, AstraZeneca entered a collaboration with Harbour BioMed, to give them the opportunity to licence immunology programmes using Harbour BioMed’s antibody technology. This technology focuses on producing multispecific antibodies that lack light chains, which would address the risk of mispairing. Collaborations and investments are accelerating research and development, in the hope of targeting more cells and bringing more treatments to shelves and hospitals. 

We have to think about how to achieve best efficacy with minimal side effects. We will not start developing a fancy technology and only later look for a potential application

 Christian Klein

However, these incredible multispecific proteins may not always provide such a helping hand. More concerningly, it is possible these therapies may trigger large immune responses that overwhelm the system, triggering dangerous side effects such as cytokine release syndrome (which can cause vast inflammation). Pairing this with the fiddly production and subpar efficiency caused by enhanced complexity of the molecules, higher-order multispecific antibodies still seem further out of reach in comparison to their bispecific counterparts.

In an interview with biotech collaborators Christian Klein and Pablo Umaña, they discussed the challenges of this technology but highlighted their passion for its development. “We have to think about how to achieve best efficacy with minimal side effects. We will not start developing a fancy technology and only later look for a potential application.” said Christian Klein, reminding us that it is crucial to evaluate the feasibility of the higher-order multispecifics. While patient safety must be prioritised, innovation is constantly improving outcomes.

Whether or not companies are overshooting with their ambition, and bispecifics are the limit, the possibility of success may be worth pursuing. Yes, there’s still far to go, but a fully realised treatment with this technology would be sensational – forever changing the drug-development landscape.