A group of researchers has developed a delivery system that identifies senescent cells and injects them with a deadly compound. This offers a potential solution to the problem of targeted delivery of senolytics .
Cellular senescence has been implicated in numerous aging-related disorders, including fibrosis, diabetes, cancer, and Alzheimer’s. Today, senolytics, drugs that remove senescent cells from tissues, are one of the most promising avenues in longevity research.
However, their development has not always been smooth. One of the problems that researchers run into is that current senolytics may not be targeted enough. Killing cells is a risky business; you don’t want to miss too often.
Right on target
The targeting issue is neither new nor restricted to senolytics. Scientists have been developing methods of targeted drug delivery to certain cell types, such as cancer cells, for decades. One of these methods is ADCs – antibody-drug conjugates. An ADC consists of a drug molecule connected to an antibody that recognizes a particular protein displayed on the surface of a target cell. When the antibody part of the molecule attaches itself to the protein, the whole ADC gets internalized by the cell and cleaved in a lysosome. Then, the antibody part is recycled, while the drug part does what it was designed to do. ADCs are already used in several approved anti-cancer medications.
By analyzing the “surfaceome” of senescent cells – i.e., the profile of proteins displayed on their surface – the researchers behind this new study had previously identified the target. It is a transmembrane protein called B2M, and it is highly expressed in senescent cells with moderate to no expression in normal cells.
Yet, senescent cells themselves are not particularly well defined, which is why the NIH has initiated the creation of an atlas of senescent cells. To begin with, there is more than one way for a cell to become senescent. One such process is replicative senescence, when after several passages (divisions), the cell gets exhausted and stops dividing. There is also stress-induced senescence caused by various types of stress – radiation, chemical, etc.
Scientists have identified several markers of cellular senescence, such as the proteins ß-galactosidase, p16, p21, and p53, but not all senescent cells express all of these markers. For instance, p53 is a hallmark of cells that underwent stress-induced senescence, while replicative senescence is better indicated by the presence of p21. B2M is expressed almost exclusively in cells that became senescent via the p53 pathway.
(Don’t) kill ’em all
The B2M-targeting ADC that the researchers developed binds to the extracellular domain of B2M via an antibody and uses the drug duocarmycin, which kills cells by inflicting heavy DNA damage. The study showed that B2M-ADCs successfully targeted cells that expressed B2M on their surface. Yet, the result was far from the total elimination of senescent cells. Rather, B2M-ADCs cleared on average 32% of p53-expressing senescent cells but, as expected, were ineffective against other senescence pathways. They also killed 6% of non-senescent cells – what the researchers thought was a negligible amount.
These results might seem underwhelming, but the fact that B2M-ADCs do not clear all or even most senescent cells might not be a bad one. Cellular senescence is a multi-faceted mechanism that participates in many important functions, such as wound healing and cancer prevention . The problems associated with aging-related cellular senescence probably emerge when too many senescent cells accumulate. The authors offer their thoughts on that too: they suggest that this might be an example of antagonistic pleiotropy – a trait or a mechanism that is beneficial earlier in life but becomes deleterious in older age. Hence, controlling the senescent cell population might be preferable to wiping it out completely, although this demands further research.
More to come
Scientists continue to perfect methods of targeted delivery and develop new ones. It is worth noting that this same group of researchers had previously proposed another method of targeted delivery of B2M to senescent cells . This method is based on molecularly imprinted polymer nanoparticles (nanoMIPs), which are essentially synthetic antibodies.
This study combines the newly identified senescence-associated surface protein B2M with a trusted method of targeted delivery – antibody-drug conjugates. Despite what might seem like less than ideal results, the idea of using senescence-associated surface proteins as targets holds a lot of promise, and this particular research constitutes an important proof of concept. As scientists learn more about senescent cells and try various combinations of drugs and delivery systems, we expect to hear good news on that front more often.
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 Poblocka, M., Bassey, A. L., Smith, V. M., Falcicchio, M., Manso, A. S., Althubiti, M., … & Macip, S. (2021). Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker. Scientific Reports, 11(1), 1-10.
 Campisi, J. (2013). Aging, cellular senescence, and cancer. Annual review of physiology, 75, 685-705.
 Ekpenyong-Akiba, A. E., Canfarotta, F., Abd H, B., Poblocka, M., Casulleras, M., Castilla-Vallmanya, L., … & Macip, S. (2019). Detecting and targeting senescent cells using molecularly imprinted nanoparticles. Nanoscale Horizons, 4(3), 757-768.
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