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How do blood samples compare to CSF samples in the analysis of brain-derived analytes?

Zetterberg教授：由于濃度低且基質復雜，測量血液中的中樞神經(jīng)系統(tǒng)衍生蛋白存在分析挑戰(zhàn)，因此在靈敏度和特異性方面對檢測提出了更高的要求。腦脊液生物標志物通常與腦病理學更密切相關，但血液生物標志物正在改善。然而，腦脊液和血漿之間的相關性最常見的保持在0.6到0.9，但不接近1，因為血液水平受到比如腎功能和流體動力學等因素的影響。

Prof Zetterberg: Measuring CNS-derived proteins in blood presents analytical challenges due to low concentrations and complex matrix, so it requires more for the test in terms of sensitivity and specificity. CSF biomarkers often correlate more closely with brain pathology, but blood biomarkers are improving. However, the correlation between CSF and plasma remain most commonly at 0,6 to 0,9, so not close to 1, since the blood levels are affected by e.g. kidney function and fluid dynamics.

一些標志物或疾病顯示在腦脊液和血漿水平之間的相關性有意想不到的斷裂。例如，GFAP在血液中比腦脊液更準確，原因目前尚不完全清楚，但可能與pH誘導的結構變化有關。此外，外周神經(jīng)病變和ALS會破壞血液與腦脊液生物標志物之間的相關性，表明獨特的疾病特異性機制。隨著我們在更大的隊列中擴大基于血液的生物標志物的使用，我們必須為意外發(fā)現(xiàn)做好準備，并繼續(xù)完善我們對它們與神經(jīng)系統(tǒng)疾病關系的理解。

Some markers, or conditions, show unexpected breakage in the correlation between CSF and plasma levels. For example, GFAP is more accurate in blood than CSF, for reasons not fully understood currently, but could possibly be linked to pH-induced structural changes. Also, peripheral neuropathies and ALS can disrupt the correlation between blood and CSF biomarkers, suggesting unique disease-specific mechanisms. As we expand our use of blood-based biomarkers in larger cohorts, we must be prepared for unexpected findings and continue to refine our understanding of their relationship to neurological diseases.

4. 在Medix Biochemica，您會使用哪些分析平臺來評估新的備選單抗？

Which assay platforms do you use in Medix Biochemica to evaluate new mAb candidates?

Galli博士：通常，我們會在熒光免疫測定中評估具有一種用銪鑭標記的測定成分的候選抗體。從我的演講中可以明顯看出，我們通常在發(fā)布前確定動力學。這些數(shù)據(jù)被添加到產(chǎn)品表中，并受到我們客戶的極大贊賞。在某些情況下，如果發(fā)現(xiàn)相關，我們也可能使用側向層析或化學發(fā)光法對備選抗體進行測試。

Emilia Galli: Typically, we would evaluate the antibody candidates in fluoroimmunoassay having one of the assay components labelled with Europium lanthanoid. As was evident from my presentation, we most often determine the kinetics before launch. This data is added to the product sheet and has been very appreciated by our customers. In some cases, we may also test candidates using lateral flow or CLIA if found relevant.

5. 還有感興趣的新興的標志物嗎？

Any emerging markers of interest?

Zetterberg教授：我認為突觸標志物真的很有趣，可能是神經(jīng)退行性病理學的有價值的早期指標。在大多數(shù)神經(jīng)退行性疾病中，突觸是第一個受損的。一旦突觸丟失，軸突就會丟失，然后最終是神經(jīng)元細胞損害。從基于血液的生物標志物中，β-突觸核蛋白和SNAP-25在反映突觸功能障礙方面顯示出前景。仍需要進行研究以更好地了解血液中突觸標志物與大腦變化之間的關系，這可以通過與神經(jīng)影像學專家合作來實現(xiàn)。

Prof Zetterberg: I think the synaptic markers are really interesting and could be valuable early indicators of neurodegenerative pathology. In most neurodegenerative diseases, the synapse is the first one to be impaired. And once the synapse is lost, the axon is lost, and then the eventually the neuronal soma. From blood-based biomarkers, beta-synuclein and SNAP-25 show promise in reflecting synaptic dysfunction. There is still research needed to better understand the relationship between synaptic markers in blood and brain changes, and this could be approached by collaborating with neuroimaging experts.

6. 您在Medix Biochemica采取了怎樣的可持續(xù)性行動？

What kind of sustainability actions do you take in Medix Biochemica?

Galli博士：感謝您提出這個重要的話題。在Medix Biochemica，我們積極關注各種可持續(xù)發(fā)展舉措，包括替代有害化學品或減少包裝中的塑料。

Emilia Galli: Thank you for bringing up this important topic. At Medix Biochemica, we are actively keeping our eyes open for various sustainability initiatives, let it be replacing harmful chemicals, or reducing plastics in our packaging.

去年，Medix Biochemica加入了EcoVadis可持續(xù)發(fā)展評級系統(tǒng)，并在我們的第一次評估中獲得了銅牌，得分超過70%的受該系統(tǒng)評級的公司。今年，我們改進了可持續(xù)發(fā)展行動，表現(xiàn)得更好，得分高于84%的公司，并再次獲得銅牌。我們表現(xiàn)最好的領域是環(huán)境、勞工與人權以及倫理。

Last year, Medix Biochemica joined the EcoVadis sustainability rating system and earned a Bronze medal on our first assessment, scoring better than over 70% of all companies rated by the system. This year, we improved our sustainability actions and performed even better, scoring better than 84% of all companies and attaining a Bronze medal again. Our top-performing areas were environment, labor & human rights, and ethics.

正如我在演講中提到的，與單克隆抗體生產(chǎn)相關的是，我們長期以來一直使用無血清培養(yǎng)基在體外生產(chǎn)單克隆抗體，這適用于雜交瘤和重組蛋白。

Related to mAb production, as I mentioned in my presentation, we have a long-standing practice of producing our mAbs in vitro with serum-free medium, which applies to hybridomas as well as recombinants.

7. 與所使用的單克隆抗體相比，檢測平臺在多大程度上影響檢測靈敏度？

To what extent does the test platform influence assay sensitivity compared to the monoclonal antibodies used?

Galli博士：抗體是許多診斷測試的關鍵。它們僅結合特定靶標提供高特異性，通過檢測樣品基質中極少量的靶分子提供高靈敏度。然而，單克隆抗體的靈敏度只能在一定程度上得到增強。靈敏度的進一步提高依賴于先進的技術。想要實現(xiàn)最佳結果需要高性能抗體和先進的、超靈敏平臺的結合。

Emilia Galli: Antibodies are the backbone of many diagnostic tests. They provide high specificity by binding only to the intended target, and high sensitivity by detecting even smallest amounts of the target molecule in sample matrix. However, the sensitivity of monoclonal antibodies can only be enhanced to a certain extent. Further gains in sensitivity rely on advanced technologies. Achieving optimal results requires a combination of high-performance antibodies and cutting-edge, ultrasensitive platforms.

例如，數(shù)字ELISA (或單分子陣列, Simoa) 新方法的靈敏度是標準ELISA的100到1000倍，能夠檢測極低濃度的生物標志物。此外，將DNA標記抗體與PCR擴增相結合的方法，例如鄰位延伸測定 (PEA)，能夠對蛋白質進行高靈敏度檢測。在PEA中，成對的DNA標記抗體與靶蛋白結合，使它們的DNA標簽靠得很近，然后可以通過聚合酶延伸。然后可以通過qPCR對DNA模板進行定量，從而精確檢測低豐度蛋白質。

For instance, novel methods like digital ELISA (or single molecule array, Simoa) can be 100 to 1000 times more sensitive than standard ELISA, enabling the detection of very low concentrations of biomarkers. Also, methods combining DNA-tagged antibodies with PCR amplification, such as Proximity Extension Assay (PEA), enable highly sensitive detection of proteins. In PEA, pairs of DNA-tagged antibodies bind to a target protein, bringing their DNA tags close together and then can be extended by polymerase. The DNA template can then be quantified by qPCR, allowing precise detection of low-abundance proteins.

另一種先進的方法是免疫沉淀質譜法 (IP-MS)，它將抗體的精確蛋白質捕獲與質譜分析相結合，以對目標分子進行高度特異性和靈敏性的檢測。

Another advanced approach is immunoprecipitation mass spectrometry (IP-MS), which pairs precise protein capture by antibodies, with mass spectrometry analysis for highly specific and sensitive detection of target molecules.

8. 在演示的早期，有兩張圖表顯示了A42/A40組合如何成為一個非常好的標記，但也列出了一個A38標記。即使與A42/A40結合使用，A38是否也不被視為可行的標記？如果是這樣，為什么不呢？

Early in the presentation there were two graphs showing how A42/A40 combined is a very good marker but there was also an A38 marker listed. Is A38 not viewed as a viable marker even when combined with either A42/A40? If so, why not?

Zetterberg教授：是的，Aβ-38非常有趣，它甚至可以保護淀粉樣蛋白級聯(lián)反應。我認為我們應該更多地研究這種β淀粉樣蛋白形式，既作為生物標志物，也可能作為干預目標 (增加其濃度可能會抑制Aβ-42纖維化)。

Prof Zetterberg: Yes, Abeta38 is very interesting and it could even be protective against the amyloid cascade. I think we should work more on this amyloid beta form, both as a biomarker but potentially also a target for intervention (increasing its concentration might inhibit Abeta42 fibrillization).

9. 應該如何看待不同的p217克隆。我猜你展示的數(shù)據(jù)都不是用Medix Biochemica克隆完成的。每個新克隆都必須在大型臨床隊列中進行驗證，還是與黃金標準的相關性就足夠了？

How should one think about different p217 clones. I guess none of the data you showed was done with the Medix Biochemica clone. Would each new clone have to be validated in a large clinical cohort or is correlation to golden standard with a few samples enough?

Zetterberg教授：是的，為了證明等效性，這可能就足夠了。為了證明優(yōu)勢，可能需要非常大的樣本群 (考慮到當前檢測的效果)。

Prof Zetterberg: Yes, to prove equivalence this could be enough. To prove superiority, really large cohorts may be needed (given how well the current assays work).