Inflammatory diseases are a significant health burden worldwide, and early diagnosis is crucial for effective management. In response to the secretion of several inflammatory cytokines including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF), the liver synthesizes a particular protein from the family of pentraxin : C-reactive protein (CRP).

C-reactive protein (CRP) was discovered in 1930 by Tillet and Francis (1) when they were investigating the properties of the serum of patients with pneumonia. They found that a protein in the serum appeared to react with the C-polysaccharide of Streptococcus pneumoniae, hence the name "C-reactive protein."

They also observed that CRP levels increased rapidly during the acute phase of inflammation and returned to baseline levels as the inflammation resolved. In fact, CRP acts as an activator of the classical complement pathway and promotes bacterial phagocytosis. This led Tillet and Francis to conclude that CRP could serve as a useful biomarker of inflammation.

C-reactive protein (CRP) is now a well-established biomarker of inflammation and infection and can be used to monitor disease progression and response to therapy. Some of the diseases for which CRP diagnosis is relevant include:

• Inflammatory bowel disease (IBD): CRP levels are often elevated in patients with IBD, and monitoring CRP levels can help to assess disease activity and response to treatment.

• Rheumatoid arthritis (RA): CRP levels can be used to monitor disease activity and response to treatment in patients with RA.

• Cardiovascular disease (CVD): CRP levels are often elevated in patients with CVD, and elevated CRP levels have been associated with an increased risk of heart attack and stroke.

• Infection: CRP levels can be used to diagnose and monitor bacterial and viral infections, including pneumonia, urinary tract infections, and sepsis. Elevated levels of CRP upon admission have been observed to be associated with increased disease severity and higher likelihood of adverse outcomes in patients with COVID-19 (2).

• Cancer: Elevated CRP levels have been observed in patients with several types of cancer, like in advanced renal cell carcinoma (aRCC), and monitoring CRP levels can help to assess response to treatment and predict prognosis.

CRP is primarily found in serum, with concentrations reaching their highest levels during some bacterial infections, increasing up to 1,000-fold. The more severe the infection or inflammation, the higher the CRP level.

By default, the following CRP values indicate whether or not inflammation is present:

• 0 - 0.50 mg/1 dL: no inflammation;
• 0.50 - 1.00 mg/1 dL: possible non-acute inflammation;
• 1.00 - 10.00 mg/1 dL: mild to moderate acute inflammation;
• above 10.00 mg/1 dL: acute and severe inflammation

However, once the stimuli cease, CRP values decrease exponentially over 18-20 hours, with a half-life of approximately 19 hours. Consequently, velocity rate measurement rather than concentration level measurement seems to be the key.

The ultrasensitive CRP assay is significantly different: it uses a different calibration scale directed towards extremely low values. At low values, above the threshold (3 mg/L), an elevated CRPus is an independent cardiovascular risk factor, in line with the current concept of atherosclerosis as an inflammatory disease. A CRPus can therefore only be interpreted in the absence of an inflammatory syndrome.

Monoclonal antibodies (mAbs) offer several advantages for CRP diagnosis in a precision medicine context. These antibodies can be highly specific and selective, allowing for accurate detection of CRP in complex biological samples. Furthermore, mAbs can be engineered to target specific epitopes on the CRP molecule, enabling the development of highly sensitive and specific assays.

The CRP protein test by monoclonal antibody replaces the sedimentation rate, the test that measures the rate at which red blood cells fall in an upright tube of blood to detect inflammation or infection. This test, although used for a long time, is no longer performed because the CRP test is more specific, reliable and sensitive. For example, ELISA assays using mAbs can detect CRP concentrations as low as 1 ng/mL.

However, accurate CRP detection can be challenging, requiring sensitive and specific assays that can distinguish between CRP and other related proteins.

CRP is a relatively small protein (~23 kDa) and has a limited number of epitopes that can be targeted by antibodies. In addition, CRP can be subject to post-translational modifications that can affect antibody binding, such as glycosylation and phosphorylation. These factors can make it difficult to generate antibodies that are both sensitive and specific to CRP.

The CRP protein sequence is also well-conserved across many different mammalian species, including humans, mice, rats, and cows.

The conservation of CRP across different species suggests that it plays an important role in host defense and inflammation, and its function has been conserved throughout evolution. The high degree of conservation also suggests that research findings in one species are likely to be relevant to other species, which can be useful in studying disease mechanisms and developing treatments.

However, there are some differences in the CRP protein sequence between different species, particularly in the region that interacts with its ligands. These differences can affect the binding specificity and affinity of CRP antibodies and assays, and can also have implications for the use of CRP as a biomarker in different species. Therefore, it is important to use species-specific antibodies and assays when studying CRP in different species.

To address these challenges, various techniques have been developed by SYnAbs to generate specific monoclonal antibodies. By using these methods, it was possible to generate high-quality antibodies that can accurately detect and quantify CRP in a variety of assays and clinical settings.

(1) Tillett WS, Francis T Jr. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med. (1930) 52:561–71.

(2) Luo X, Zhou W, Yan X, Guo T, Wang B, Xia H, Ye L, Xiong J, Jiang Z, Liu Y, Zhang B, Yang W. Prognostic Value of C-Reactive Protein in Patients With Coronavirus 2019. Clin Infect Dis. 2020 Nov 19;71(16):2174-2179. doi: 10.1093/cid/ciaa641. PMID: 32445579; PMCID: PMC7314209.