Back in the 1990s, a cell phone performed one function. You dialed a number and placed a call. Now, smartphones have cameras, maps, music players, and more, offering multiple functions all rolled into one. In medicine, many treatments are still stuck in the brick phone era: one drug for one job. But the rise of bispecific antibodies (BsAbs) has ushered in the smartphone age for therapeutics, and the possibilities are exciting.
However, as with all innovative leaps, the challenge lies in the details. Developing BsAbs requires comprehensive knowledge of their mechanisms of action, pharmacokinetic (PK) characteristics, and the best strategies to ensure a smooth path to market. Sponsors must overcome these hurdles to bring effective BsAbs to market in the most efficient manner possible.
Bispecific Antibodies: Promise and Challenges
Regulators approved the first BsAb for use in the United States in 2009, but their development has been the result of decades of steady progress. The concept was first introduced in the 1960s, and technological breakthroughs in the following decades pushed the idea towards reality. To date, regulators have approved around 20 BsAbs across the globe, most of which target cancers.
BsAbs have a unique design that allows them to perform two functions simultaneously. This enables novel therapeutic mechanisms such as redirecting immune cells to tumor cells, shutting down several disease signals, and focusing treatment precisely where it’s needed.
This dual-targeting capability offers promise in oncology, ophthalmology and immunology. However, BsAbs present complex development challenges that further intensify regulatory scrutiny due to their structural diversity, immunogenicity risks, and the need for precise target engagement. Overcoming these hurdles requires careful consideration and deliberate deployment of testing methodologies to ensure safety, efficacy, and consistency throughout the product lifecycle.
1. Master the Mechanisms of Action of Bispecific Antibodies
Bispecific antibodies have challenged conventional drug development paradigms throughout their four primary mechanisms of action have emerged. Understanding them is critical for us to better guide study design.
Bispecific T cell engagers
This type of BsAb acts like a matchmaker. It simultaneously binds to the T cell receptor and the cancer cell, forming a synapse between the two cell types. This activates T cells, which release the necessary molecules to kill tumor cells.
Immune checkpoint (ICP) modulation
Another type of BsAbs work by blocking a cancer’s ability to shut down the body’s immune system. These include some that dual-block ICP, and others that target ICP simultaneously with a target involved in other signaling pathways.
Signaling pathway blockade
These target faulty signaling inside cells. BsAbs can block two signaling pathways at once, or they can bind to two different parts of the same target.
Functional mimicry
This type of BsAb is designed to act like a natural helper in the body, guiding molecules into the right spot to ensure a function occurs properly.
2. Carefully Consider Dosing and Interactions of Bispecific Antibodies
Setting the right starting dose is critical when designing human trials of BsAbs. Some products already in the market behave predictably at higher doses, but at lower doses become less consistent. Past clinical trials have shown that if a drug over activates T-cells, it can trigger a dangerous immune reaction called a cytokine storm. Researchers often use the Minimum Anticipated Biological Effect Level (MABEL) method to avoid this by setting very cautious first-in-human doses.
To further mitigate the risk of a cytokine storm, developers might consider using pretreatments before administration of BsAbs. In addition, clinical recommendations for stepwise dose escalation can also potentially reduce the risk of cytokine storm. Despite these precautions, some BsAb drugs have been released with a boxed warning.
3. Establish Robust ADME Testing for Bispecific Antibodies
Drug developers must also overcome challenges caused by the complex properties of BsAbs. Appropriate Absorption, Distribution, Metabolism, and Excretion (ADME) testing can address these considerations by taking into account key lessons learned from previous BsAbs development.
- Absorption: BsAbs have poor stability in the gastrointestinal tract and suffer from low permeability across the gut wall. This gives them extremely poor oral bioavailability. As a result, most are administered via injection. The bioavailability through the non-IV route is generally good. For example, the bioavailability of elranatamab is 56% after subcutaneous injection; The bioavailability of emicizumab is 80%-93% after subcutaneous injection.
- Distribution: Similar to monoclonal antibodies, BsAbs remain in the circulatory system and extracellular fluids due to their large molecular size, limiting their ability to enter cells and deep tissues.
- Metabolism and Excretion: Because of their protein-based nature, bispecific antibodies don’t use the usual drug-metabolizing enzymes (like CYP450), so their metabolism and excretion are usually not a major concern in safety testing. Similar to the monoclonal antibody, BsAbs show different dosage linearity from small molecules. For example, when the dose of amivantamab is ≥20 mg/kg/week, the systemic exposure in cynomolgus monkeys is linear, but it presents non-linear PK when the dosage is < 20 mg/kg/week. which may be contributed by target-mediated drug disposal (TMDD).
4. Choose the Correct Bioanalysis Techniques
Due to the structural complexity of BsAbs, researchers primarily use ligand-binding assay platform for their bioanalysis. This tool can detect the total amount of antibody, individual targets, or the fully intact antibody.
Occasionally, more than one method is required because intact bispecifics and fragments are both active forms. U.S. regulators recommend using multiple approaches to get the complete picture, which is better to interpret the PK/PD relationship.
For newer BsAb designs, such as probodies, ligand-binding assays may not be adequate, as they produce active forms after metabolism. In this case, liquid chromatography-mass spectrometry (LC-MS), may be more suitable as they can detect surrogate peptides. 5. Prepare for Immunogenicity Challenges
The artificial structure of BsAbs increases immunogenicity risks such as the formation of anti-drug antibodies (ADAs), which can induce severe drug-related toxicity.
This is also a risk when developing BsAbs targeting solid tumors, and many immunotherapeutic applications for cancer have discontinued clinical development due to the formation of ADAs.
Immunogenicity studies for BsAbs are best tailored to a specific research phase. In early preclinical studies, analyzing total ADAs helps interpret PK and TK data. During the IND stage, analysis of immunotoxicity and immune cell profiling is most helpful. And in clinical research phases, further assessments of immunotoxicity or neutralizing antibodies (Nabs) may be required.
A Final Word
BsAbs offer many advantages to researchers looking for new tools to fight debilitating and devastating diseases. Their unique nature allows for dual-targeting in a single molecule, and they can reduce off-target toxicity, enhance efficacy, and improve safety.
Of course, there are challenges in their development. Developers must carefully monitor the risk of cytokine storms, monitor drug interactions, and establish robust testing to ensure these drugs are as effective as possible. But forward-looking sponsors, who engage with partners boasting a wealth of experience, expertise, and know-how, will be able to ensure each therapeutic candidate is rigorously characterized, safe, and ready for regulatory advancement.
