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BispecificADC is an active frontier, and today we will discuss whether bispecificADC is more effective than traditional monoclonal ADC in tumor toxin enrichment.

Bispecific antibodies can be divided into two main categories: one type binds to two different antigens on different cells, acting as a connector, such as several marketedCD3 connectors and connectingIX withX factor emicizumab. The other type binds to two different epitopes of the same antigen on the same cell surface or two different antigens, such as HER2 bispecific antibodies zanidatamab and EGFRxcMET bispecific Amivantamab.

Bispecific antibodies have different pharmacological effects compared to monoclonal antibodies, so when made into ADC, the activity and safety will also differ from monoclonal ADC. However, today we mainly discuss the distinction in drug distribution; bispecific ADC primarily aims to leverage the thermodynamics of antibody-antigen binding to achieve greater tissue distribution advantages and further enhance tumor toxin enrichment.

The antigen-driven distribution of antibody drugs is similar to job hunting; different regions attract different talents due to industrial characteristics. The Yangtze River Delta has concentrated life science talents, while Shenzhen Bay has gathered IT talents.

The distribution differences between bispecific and monoclonal antibodies are akin to a couple job hunting together versus a single person job hunting alone. A single person can go anywhere there are jobs, but a couple needs to find jobs in the same city that cater to both their needs; otherwise, one of them will be unemployed (the two-body problem), translating to drug design means that bispecific antibodies become monoclonal antibodies, failing to achieve the design goal.

However, if there are indeed jobs for both types in the same city, the chances of both staying in that city are greater than for a single employee.

Not only does the less satisfied party (low affinity) have to compromise, but the highly matched party (high affinity) will not easily quit due to the other party’s job situation. This is known as the avidity effect, and bispecific ADC aims to achieve this design goal.

If the two antigens of the bispecific antibody are not on the same cell, the distribution situation becomes more complex, similar to two people each having very satisfying jobs, but those jobs are not in the same city, meaning they can only split their time between two places, affecting enrichment in the target city.

For example, if the HER2xCD3 bispecific antibody has only HER2 antibody with high affinity and CD3 antibody with low affinity, it will enrich in HER2 positive tumors. If the CD3 antibody also has high affinity, some will be diverted to T cell-enriched tissues.

This type of bispecific antibody is not the mainstream in ADC drug design. For heterogeneous tumors, some cells may express antigen A, while others express antigen B, and AxB bispecific antibodies can deliver toxins to these two types of tumor cells, but they do not have advantages compared to combination therapies, which is not the focus of this article.

Some bispecific antibodies utilizing transport proteins like TfR do not rely on antigen distribution to influence drug distribution, and this article will not discuss them either.

So, do bispecific antibodies targeting different tumor antigens on the same cell have better toxin enrichment in tumors than monoclonal ADC? We will analyze this strategy using EGFRxcMET bispecific antibody Amivantamab as an example, as these are two tumor-associated antigens expressed simultaneously in tumor cells.

The toxin distribution of EGFRxcMET ADC has not been studied in detail, but a recent study on the distribution of the radioactive isotope 89Zr labeled EGFRxcMET bispecific antibody ([89Zr]ZrDFO-Amivantamab) in mouse tumor models can extrapolate the toxin enrichment effect of bispecific ADC.

There are two important factors to consider: first, radioactive transition metal ions usually require ligands with high polarity for complexation and have poor membrane permeability, so they may not be able to leave the releasing cells after unloading from the antibody.

Therefore, the distribution of bispecific imaging agents cannot completely replicate the bystander killing effect of ADC toxins (modern universal toxins) in tissue distribution, as the former finds it difficult to escape from tumor tissues.

Using the job hunting analogy, the distribution of imaging agents is more like tracking your job interview trajectory rather than the actual job trajectory.

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Another factor to consider is that Amivantamab does not bind to mouse EGFR or cMET, so the mouse model will exaggerate tumor enrichment (in humans, it will bind to healthy tissue targets, leading to more severe off-target toxic effects).

First, let’s look at the distribution of this imaging agent in tumors and normal tissues over time. It is evident that tumors have enriched more bispecific labeled drugs compared to normal tissues. However, the degree of enrichment is not significant, especially considering the factor that normal tissue antigens in mice have no affinity for the bispecific antibody.

Next, let’s examine the differences in enrichment of this imaging agent in tumors with different antigen expression levels. In EGFR high, medium, and low expression tumors, the 89Zr concentration also shows a gradient decrease, indicating that there is target-mediated drug distribution.

Although this 5x enrichment is not stunning, it is still a help for chemotherapeutic toxins with a therapeutic window of <1.

Compared to untargeted IgG-ADC, bispecific ADC has a stronger enrichment capability, further proving target-mediated drug distribution.

Compared to monoclonal antibodies, bispecific antibodies show more significant enrichment in tumors, but the difference is only 2-3 times. Therefore, even in a clean background mouse model (where healthy tissue antigens do not affect distribution), the enrichment of bispecific ADC compared to monoclonal ADC exceeds that of monoclonal ADC in double-positive antigen cells, but the effect is not very significant.

Moreover, this is a poorly membrane-permeable ADC itself or ionic complex, and the enrichment of freely membrane-permeable toxins may be even less significant due to the escape effect of toxins, which still leaves a gap from the target of 10x ADC.

Additionally, although bispecific antibodies show higher tumor enrichment than monoclonal antibodies compared to some normal tissues, they may show a decrease compared to others. If we consider the impact of normal tissue antigen expression in actual tumor patients, predicting the therapeutic window becomes more challenging.

Therefore, although bispecific ADC shows certain advantages over traditional ADC, it is not an overwhelming advantage, and a relatively strict screening system is needed to select those bispecific ADC that can truly enrich toxins better than monoclonal antibodies.

[1] Cavaliere, Alessandra, et al. “Development of [89 Zr] ZrDFO-amivantamab bispecific to EGFR and c-MET for PET imaging of triple-negative breast cancer.”European journal of nuclear medicine and molecular imaging 48 (2021): 383-394.

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