LMB-2 / National Cancer Institute - LARVOL DELTA

LMB-2 to Treat Hairy Cell Leukemia (clinicaltrials.gov) - P2 | N=15 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Mar 2024 ➔ Dec 2022

Trial completion • Trial completion date • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • Neutropenia • Oncology • BRAF

Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia (clinicaltrials.gov) - P1/2 | N=18 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Phase classification: P2 ➔ P1/2

Phase classification • Trial completion • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Oncology

Podocytes are lost from glomeruli before completing apoptosis. (PubMed, Am J Physiol Renal Physiol) - "To investigate this discrepancy, we analyzed the dying process of podocytes in vitro and in vivo using LMB2, a human (h) CD25-directed immunotoxin...These results indicate that upon activation of apoptotic caspases, podocytes are detached and lost in the urine before nuclear fragmentation and that the physical force of glomerular filtration facilitates detachment. This phenomenon may be the reason why definitive apoptosis is not observed in podocytes in vivo."

Journal • Nephrology • Renal Disease • BAK1 • CASP3 • IL2RA

LMB-2 to Treat Hairy Cell Leukemia (clinicaltrials.gov) - P2 | N=15 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2022 ➔ Mar 2024

Trial completion date • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • Oncology • BRAF

Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia (clinicaltrials.gov) - P2 | N=18 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2021 ➔ Dec 2024

Trial completion date • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Oncology

LMB-2 to Treat Hairy Cell Leukemia (clinicaltrials.gov) - P2; N=15; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Mar 2021 ➔ Mar 2022

Clinical • Trial completion date • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • Neutropenia • Oncology • BRAF

Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia (clinicaltrials.gov) - P2; N=18; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Dec 2020 ➔ Dec 2021

Clinical • Trial completion date • Hematological Malignancies • Leukemia • Oncology

Tubulointerstitial fibrosis can sensitize the kidney to subsequent glomerular injury. (PubMed, Kidney Int) - "...At week seven, all mice were given the immunotoxin LMB-2, which binds to CD25 to induce podocyte injury...This supports the concept that even mild preexisting tubulointerstitial injury sensitizes glomeruli to subsequent podocyte-specific injury. Thus, increased atubular glomeruli and abnormal tubuloglomerular feedback significantly contribute to the crosstalk between the tubulointerstitium and glomeruli."

Biomarker • Journal • Biosimilar • Diabetic Nephropathy • Fibrosis • Immunology • Renal Disease

Hypoxia-Inducible Factor Agonist Ameliorates Impact of Tubulointerstitial Injury on Subsequent Glomerular Injury (KIDNEY WEEK 2016) - "Uninephrectomy was performed at wk 6 to assess extent of tubulointerstitial fibrosis, and LMB2 was injected at wk 7. Mice with FA+podocyte injury showed increased mortality, which was also reduced by DMOG (FA+DMOG 14.3 vs. FA 55.6% death rate), linked to improved renal function. Our findings indicate that hypoxia contributes to tubular injury sensitizing to subsequent glomerular injury, and restoring HIFs may blunt this adverse crosstalk of tubules to glomeruli."

Biosimilar • Fibrosis • Immunology • Renal Disease

Suppression of a tomato SEPALLATA MADS-box gene, SlCMB1, generates altered inflorescence architecture and enlarged sepals. (PubMed, Plant Sci) - "Yeast two-hybrid assay showed that SlCMB1 could interact individually with MC, J, AP2a and SlMBP21. Overall, our results indicate that SlCMB1 is an important regulator involved in the development of inflorescence architecture and sepal size in tomato plants."

Journal • Biosimilar

Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia (clinicaltrials.gov) - P2; N=17; Suspended; Sponsor: National Cancer Institute (NCI); Trial primary completion date: Oct 2015 ->Dec 2016

Trial primary completion date • Biosimilar • Hematological Malignancies • Inflammation • Leukemia • Oncology

Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia (clinicaltrials.gov) - P2; N=18; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Oct 2019 ➔ Dec 2020

Clinical • Trial completion date

Outcome of relapse in children and adolescents with B-cell non-Hodgkin lymphoma and mature acute leukemia: A report from the French LMB study. (PubMed, Pediatr Blood Cancer) - "Survival of children/adolescents with mature B-cell lymphoma/leukemia remains poor after relapse with no apparent improvement with rituximab. Response rates to salvage chemo-immunotherapies are insufficient and new drugs are urgently needed to improve disease control."

Clinical • Journal

Recombinant immunotoxins for hematologic malignancies (AACR-NCI-EORTC 2019) - "Recombinant immunotoxins are similar to but distinct from growth-factor fusions toxins like denileukin diftitox and Tagraxofusp, FDA-approved in 1999 and 2018, respectively...Anti-CD25 recombinant immunotoxin LMB-2 was active in several hematologic malignancies, notably hairy cell leukemia (HCL) and adult T-cell leukemia (ATL)...Improved targeting of HCL was achieved with anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox (Moxe) that was stabilized with a disulfide bond in the Fv and has a high affinity for CD22...Molecular remissions assessed by blood analysis may be useful to determine the number of cycles of Moxe to administer to achieve long-term CR or possibly cure. To achieve molecular remissions with fewer cycles, Moxe is being tested with rituximab to facilitate tumor reduction and decrease anti-drug antibody formation."

Biphasic MIF and SDF1 Expression Promotes CD44-Mediated Glomerular Parietal Epithelial Cell Migration in Focal Segmental Glomerulosclerosis (KIDNEY WEEK 2019) - "Methods NEP25/LMB2 mice, the toxin-induced podocyte injury model, were used (n=5)...In vitro, MIF and SDF1 individually induced CD44 and CXCR4 on mPECs and promoted their migration which was inhibited by CD44 knockdown. Conclusion Biphasic expression of MIF and SDF1 in podocytes and PECs, and roles of these chemokines in PEC activation in vitro suggested that CD44-mediated PEC migration might be initiated by MIF and SDF1 and sustained through their paracrine and autocrine effect."

Integrin β6 Knockout Ameliorates Glomerular Sensitization to Podocyte-Specific Injury (KIDNEY WEEK 2019) - "Methods Wild type (WT) or β6-/- mice were mated with NEP25 mice which express human CD25 on podocytes that can be injured with specific toxin (LMB2) injection...We postulate that β6 may, in addition to effects on tubulointerstitial injury, also modulate macula densa function. Funding NIDDK Support"

Kidney Organoid Model of Selective Podocyte Injury (KIDNEY WEEK 2019) - "Selective podocyte injury can be induced by the hCD25-targeted immunotoxin, LMB2...This organoid system will be a powerful tool for investigating mechanisms underlying podocyte injury. Funding Government Support - Non-U.S."

Loss of Ubiquitin-Specific Protease 40 in Podocyte Enhances Kidney Injury (KIDNEY WEEK 2019) - "To explore the role of USP40 in podocyte injury, we crossed USP40KO with NEP25 mice, in which selective podocyte injury can be induced by injection with an immunotoxin, LMB2...Finally, apparent protein binding of USP40 with CRT, but not with BIP, was observed. Conclusion USP40 may be involved in a self-defense mechanism in podocyte injury probably through interacting with CRT."

P2X7 Expressed in Injured Podocytes May Spread the Kidney Injury Through Caspase 3 (KIDNEY WEEK 2019) - "Background We previously generated a mosaic mouse model in which a fraction of podocytes express hCD25 and can be injured by a hCD25-directed immunotoxin, LMB2...Caspase-3 inhibitor significantly attenuated the leakage of EGFP induced by ATP (26.4±2.6 vs 37.9±3.3%), whereas Caspase-1 inhibitor did not (37.0±3.0%). Conclusion These results indicate that injured podocytes express P2X7, which may further augment injury by inducing caspase-3 dependent apoptosis."

Extent of Glomerular Filtrate Determines the Pattern of Podocyte Detachment (KIDNEY WEEK 2019) - "Up to some threshold, increase in glomerular filtrate may enhance the tendency of the lesion as a local event. Excessive glomerular filtrate beyond the autoregulation by glomerulus, as presumed in LMB2+UNx model in the study, may change the pattern of podocyte detachment that accelerates FSGS."

Angiotensin II Receptor Blocker Blocks Spreading Podocyte Damage in a Partial Podocytectomy Model (KIDNEY WEEK 2019) - "After the injection with hCD25-targeting immunotoxin, LMB2, not only hCD25-positive but also hCD25-negative podocytes were injured, and the mice developed global sclerosis...Conclusion Thus, our mosaic mouse model can visualize and evaluate secondary podocyte injury, and we have herein demonstrated that ARB attenuates the secondary podocyte injury. Funding Government Support - Non-U.S."

Improving the in vivo efficacy of an anti-Tac (CD25) immunotoxin by Pseudomonas exotoxin A domain II engineering. (PubMed, Mol Cancer Ther) - "...LMB-2 is an extremely active anti-Tac recombinant immunotoxin composed of an Fv that binds to Tac and a 38-kDa fragment of Pseudomonas exotoxin A (PE38)...Both of these improvements led to significantly increased anti-tumor efficacy in vivo. We conclude that the next generation anti-Tac immunotoxin is an improved candidate for targeting Tac expressing malignancies."

IO Biomarker • Journal • Preclinical

LMB-2 to Treat Hairy Cell Leukemia (clinicaltrials.gov) - P2; N=15; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Mar 2019 ➔ Mar 2021

Clinical • Trial completion date

Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia (clinicaltrials.gov) - P2; N=18; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Jan 2019 ➔ Oct 2019

Clinical • Trial completion date

"Great @Clmb2CnqrPhx today! Nice weather recovery.🌤️🌵 Thank you for supporting the event @apsFYI #ClimbPhx @AmericanCancer" (@timmer_rebecca)