Generation of a Fully Human High Affinity Neutralizing Antibody Against MT-SP1/Matriptase and Its Potential Role for the Treatment of B Cell Lymphoma.
Bibliographic record
Abstract
Abstract Membrane-type serine protease 1 (MT-SP1)/Matriptase is a type II transmembrane serine protease that is primarily expressed in epithelial cells and is over-expressed in several cancers. MT-SP1 has been implicated in the processes of tumor cell invasion and metastasis, primarily due to its ability to degrade extracellular matrix proteins and to activate the latent forms of hepatocyte growth factor (HGF), urokinase type plasminogen activator and protease-activated receptor 2. To further explore the role of this protein in human cancer, we developed a fully human IgG1, high affinity, neutralizing antibody against MT-SP1 (95/96) using XenoMax® technology. Using this antibody, we confirmed the expression of MT-SP1 on epithelial cells. In addition, we observed MT-SP1 expression on human peripheral blood B lymphocytes and monocytes. Furthermore, expression was also observed on several B cell lymphomas including Ramos, Raji and Daudi cell lines where, in contrast to epithelial cells, MT-SP1 was found in the absence of its inhibitor and cognate receptor, HGF activator inhibitor -1 (HAI-1). As 95/96 is a potent inhibitor of MT-SP1 enzymatic activity, we used the antibody to examine the functional role of MT-SP1 in B cell lymphoma. Using a tripeptide fluorogenic substrate of MT-SP1, we detected cell surface enzymatic activity on Ramos cells that was completely inhibited by 95/96, implying that the MT-SP1 expressed on Ramos cells is catalytically active. The ability of 95/96 to modulate the invasive properties of Ramos lymphoma cells was evaluated using a rodent hind-limb paralysis model. The median survival of SCID mice systemically inoculated with Ramos lymphoma cells, and receiving 95/96, was significantly extended compared to the animals receiving an isotype-matched control antibody (35 days vs. 26 days, p < 0.01). 95/96 had no effect on the in vitro proliferation or invasion of Ramos cells and was unable to induce cell death in a whole blood assay or by complement-dependent cytolysis. Collectively, these data suggest a role for MT-SP1 catalytic activity in the invasion or metastasis of Ramos B cell lymphoma.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".