Amelioration of Immune Thrombocytopenia in Human CD44 Transgenic Mice By Anti-Human CD44 Antibodies
Bibliographic record
Abstract
Abstract Selected monoclonal antibodies to murine CD44 are able to successfully ameliorate murine immune thrombocytopenia (ITP) and other inflammatory diseases at a 3 log fold lower dose than IVIg. Since not all murine CD44 antibodies were successful and, like IVIg, the anti-inflammatory mechanism involved is speculative, progress toward human antibodies has been stymied. To potentially develop a therapeutic antibody for patients, we generated transgenic mice expressing the extracellular and transmembrane sequences of human CD44 linked to the murine intracellular CD44 sequence (huCD44) with knockout of murine CD44. Flow cytometric analysis revealed that these mice express huCD44 on leukocytes, but not on platelets or red blood cells. HuCD44 mice injected with the anti-platelet antibody MWReg30 develop significant thrombocytopenia comparable to normal mice. Utilizing the huCD44 mouse model, we tested 5 monoclonal antibodies reactive with human CD44 of different isotypes; mouse IgG1, mouse IgG2a, mouse IgG2b, rat IgG2a, and rat IgG2b. We report here that pretreatment of mice with all of these antibodies, with the exception of the mouse IgG2b clone all ameliorated thrombocytopenia to the same extent as IVIg, but given at a 3 log-fold lower dosage than IVIg. Interestingly, the mouse IgG2b antibody that was not successful bound to white blood cells as well as the successful antibodies. When mice were re-injected with anti-platelet antibody 24 hr post anti-huCD44 antibody injection, they were still protected from thrombocytopenia at 48 hr, suggesting that these antibodies exhibit durable protection. The clinical effectiveness of these antibodies does not appear to be related to their extent of huCD44 binding or IgG subtype. In addition, the effectiveness of these antibodies may not be restricted or related to specific activating IgG Fc receptors (FcγR) as the successful mouse IgG1 subtype is only known to interact with FcγRIII, while the IgG2b subtype can bind activating FcγRI, III and IV with only one-of-two of this subtype having therapeutic activity. In conclusion we have developed, to our knowledge, the first huCD44 transgenic mouse and demonstrate herein that selected antibodies to huCD44 can ameliorate immune thrombocytopenia. These data suggest that some anti-CD44 antibodies may offer a new therapeutic modality for patients with ITP. Disclosures No relevant conflicts of interest to declare.
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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 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".