October 2021

The current research behind bispecific antibodies brings hope to the possibility of creating more personalized and effective treatment options for cancer patients. Bispecific antibodies are genetically engineered antibodies that are designed to simultaneously bind various tumor antigens as well as T cells, resulting in tumor suppression via concurrent inhibition of multiple targets [1].

Research groups at Johns Hopkins University have successfully created bispecific antibodies which target mutant tumor suppressor proteins including p53 and RAS. Mutations in both TP53 and RAS tumor suppressor genes are known to be significant contributors to many types of cancers, including but not exclusive to ovarian, esophageal, pancreatic, colorectal, and lung cancer. The fact that bispecific antibodies have shown to target mutated tumor suppressor proteins without affecting the function of these proteins in normal, non-cancerous cells, truly brings hope to the advancement of cancer treatment. Although the low level of expression of mutant tumor suppressor proteins has been a recurring obstacle in cancer research, it has not been an issue for bispecific antibodies, as they have been found to successfully activate T cells even with extremely low levels of p53 and RAS targets [2][3].

However, there are certain challenges that researchers must overcome in order to develop bispecific antibodies into off-the-shelf immunotherapeutic medications. With bispecific antibodies being small molecules with short half lives, they must be continuously infused into the bloodstream in order to observe the therapeutic effect [3]. The attempt to increase drug half life via the addition of other elements presents a dilemma, as it leads to a decrease in drug potency. 

Despite the presence of these challenges, the research behind bispecific antibodies for the treatment of cancer brings a lot of hope to the field of medicine. Bispecific antibodies being able to selectively target some of the major genes that are associated with cancer pathogenesis reveals a revolutionary approach in improving the treatment of a significant number of cancers.

References:

[1] Weidanz J. Targeting cancer with bispecific antibodies. Science. 2021;371(6533):996-997. doi/10.1126/science.abg5568 

[2]  Douglass J, Hsiue EH, Mog BJ, et al. Bispecific antibodies targeting mutant RAS neoantigens. Sci Immunol. 2021;6(57):eabd5515. doi:10.1126/sciimmunol.abd5515

[3] Hsiue EH, Wright KM, Douglass J, et al. Targeting a neoantigen derived from a common TP53 mutation. Science. 2021;371(6533):eabc8697. doi:10.1126/science.abc8697

Aging is a natural biological process that occurs in the cells, tissues, and organ systems of the body and affects their ability to maintain and restore homeostasis. The kidneys, which are primarily responsible for the disposal of waste products and toxins and to produce urine, have been widely studied to learn more about age-related loss [1]. 

The hallmarks of kidney aging are characterized by changes in renal structure and function. There is reduced blood flow to the kidneys due to reduced production of nitric oxide, which produces renal vasodilation. A decrease in renal volume and the number of functioning glomeruli and nephrons results in a decreased glomerular filtration rate (GFR) [2][3]. It is estimated that the GFR slowly begins to decline around 30-40 years of age, and is further accelerated once we reach 65-70 years [3]. The culmination of these defining factors increases susceptibility of kidney injury and disease, as well as enhances the risk for other comorbidities and adverse drug reactions. 

Although physiology and anatomy are well understood, relatively little is known about the molecular processes that mediate the age-related phenomenon in kidneys. Most research performed thus far has looked at the transcription of genes into proteins. However, a study published earlier this year by eLife found that changes in protein levels do not correspond to changes in mRNA levels. Researchers examined kidney function and measured mRNA and protein expression in the kidneys of genetically diverse mice over the course of 18 months, leading them to conclude that changes in proteins are not all regulated by gene transcription. Rather, their findings indicate that changes in proteins occur post-transcriptionally, and that may be attributed to changes in translational efficacy or protein turnover rates [4]. 

These changes in protein and mRNA homeostasis contribute to an increase in both the inflammatory response and immune cell infiltration into the kidney, particularly of B-lymphocytes and macrophages. Additionally, there is observance of marked mitochondrial dysfunction [4]. This relates to the prevalent mitochondrial theory of aging, which postulates that a decrease in cell energy production is caused by loss of mitochondrial integrity, oxidative damage, and mitochondrial DNA mutations [5].  

By demonstrating that gene expression does not correlate to protein expression, the greater implications of this study propel forward the idea that these variables should be studied both independently and interdependently in order to gain a more comprehensive understanding of aging. The developments of this study could be beneficial in paving the way for future therapeutics designed to combat pathologies associated with kidneys and other vital organs. 

References:

[1] Khan, S.S., Singer, B.D. and Vaughan, D.E. (2017), Molecular and physiological manifestations and measurement of aging in humans. Aging Cell, 16, 624-633. https://doi.org/10.1111/acel.12601

[2] Denic, A., Glassock, R. J., & Rule, A. D. (2016). Structural and Functional Changes With the Aging Kidney. Advances in chronic kidney disease, 23(1), 19–28. https://doi.org/10.1053/j.ackd.2015.08.004

[3] Kanasaki, K., Kitada, M. & Koya, D. (2012). Pathophysiology of the aging kidney and therapeutic interventions. Hypertension Research, 35, 1121–1128. https://doi.org/10.1038/hr.2012.159

[4] Takemon, Y., Chick, J. M., Gerdes Gyuricza, I., Skelly, D. A., Devuyst, O., Gygi, S. P., Churchill, G. A., & Korstanje, R. (2021). Proteomic and transcriptomic profiling reveal different aspects of aging in the kidney. eLife, 10, e62585. https://doi.org/10.7554/eLife.62585

[5] Bratic, A., & Larsson, N. G. (2013). The role of mitochondria in aging. The Journal of clinical investigation, 123(3), 951–957. https://doi.org/10.1172/JCI64125