CD45-targeted antibody-drug-conjugate successfully conditions for allogeneic hematopoietic stem cell transplantation

Blood ◽  
2022 ◽  
Author(s):  
Asim Saha ◽  
Sharon Hyzy ◽  
Tahirih Laforest Lamothe ◽  
Katelyn J. Hammond ◽  
Nicholas M Clark ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Tissue Injury ◽  
Single Agent ◽  
Curative Treatment ◽  
Hematopoietic Stem ◽  
Antibody Drug

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with non-malignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current genotoxic conditioning regimens mediate tissue injury and potentially incite and amplify GVHD, limiting use of this potentially curative treatment beyond malignant disorders. Minimizing genotoxic conditioning while achieving alloengraftment without global immune suppression is highly desirable. Antibody-drug-conjugates (ADCs) targeting hematopoietic cells can specifically deplete host stem and immune cells and enable alloengraftment. Here we report an anti-mouse CD45-targeted-ADC (CD45-ADC) that facilitates stable murine multi-lineage donor cell engraftment. Conditioning with CD45-ADC (3mg/kg) was effective as a single agent in both congenic and minor-mismatch transplant models resulting in full donor chimerism comparable to lethal total body irradiation (TBI). In an MHC-disparate allo-HSCT model, pre-transplant CD45-ADC (3mg/kg) combined with low-dose TBI (150cGy) and a short course of costimulatory blockade with anti-CD40 ligand antibody enabled 89% of recipients to achieve stable alloengraftment (mean value: 72%). When CD45-ADC was combined with pre-transplant TBI (50cGy) and post-transplant Rapamycin, Cytoxan or a JAK inhibitor, 90-100% of recipients achieved stable chimerism (mean: 77%, 59%, 78%, respectively). At a higher dose (5mg/kg), CD45-ADC as a single agent was sufficient for rapid, high level multi-lineage chimerism sustained through the 22 weeks observation period. Therefore, CD45-ADC has potential utility to confer the benefit of fully myeloablative conditioning but with substantially reduced toxicity when given as a single agent or at lower doses in conjunction with reduced intensity conditioning.

Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis with Myeloid Metaplasia (MMM) - Transplantation Should Be Performed before Transfusion Dependence Occurs.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1513-1513
Author(s):  
Herrad Baurmann ◽  
Irina Burlakowa ◽  
Joerg Kaltenhaeuser ◽  
Dirk Judith ◽  
Mansoor Heshmat ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Treatment Option ◽  
Risk Score ◽  
Curative Treatment ◽  
Unrelated Donor ◽  
Hematopoietic Stem

Abstract Introduction: MMM is a clonal myeloproliferative disorder of later life with a wide range of life expectancy from months to many years. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option, however associated with considerable morbidity and mortality. We analyzed the results of HSCT in 15 consecutive patients (pts) with MMM referred to our institution during the last four years in order to determine the best time point for transplantation. Patients and Methods: Ten males and five females with primary (n = 13) and secondary MMM following myeloproliferative syndrome (n = 2) were grafted with unmanipulated bone marrow (n = 10) or peripheral stem cells (n = 5) from a related (n = 6) or unrelated (n = 9) donor. Median (md) age was 49 (36 – 64) years, md time from diagnosis to transplant 27 (6 – 132) months. Five pts had low, eight intermediate and two high risk disease (Dupriez score 0, 1, 2). All intermediate risk pts were categorized Dupriez 1 because of hemoglobin levels (Hb) < 10 g/dl. In low risk pts indication for transplant were severe constitutional symptoms. Mean risk score was 0.4 (0–1) in related and 1.1 (0–2) in unrelated transplants. 8 pts were transfusion dependent and two had portal hypertension. Eleven pts received a conditioning of intermediate intensity containing TBI(8Gy)/Flud/Cy (n = 10) or Bu(12)/Flud (n = 1). Four pts had standard TBI/Cy or Bu/Cy (n = 2 each). GvHD prophylaxis consisted of CsA and short course MTX. In all unrelated and two related transplants rabbit ATG (Genzyme n = 6, Fresenius n = 5) was added before grafting. Results: All pts engrafted at a md of 23 (11 – 28) days. Four pts developed extended cGvHD. Four pts died at a md of 266 (177–407) days: One from liver cirrhosis, one from cerebral aspergillosis and two from infections associated with cGvHD. At a md follow up of 21 (4 – 53) months probability of disease free survival (DFS) is 66% for the whole cohort and 100% vs 45% for pts with a related versus an unrelated donor. Results of MUD transplants are confounded with the higher risk score of pts grafted from an unrelated donor, as DFS according to disease risk was 100% for score 0 and 52% for score 1 and 2. Need for red blood cell transfusions before transplant was an even better predictor of DFS with 100% in untransfused and 36% in transfusion dependent pts. A log rank test was performed for the following variables: Conditioning intensity, donor type (MUD vs MRD), stem cell source, Dupriez score and need for blood transfusions: Only transfusion dependence proved to be significant (p = 0.03). Conclusions: Although the number of pts is small our results support the use of related and unrelated allogeneic SCT as a curative treatment option in MMM. Hb below 10 g/dl has been reported to be a predictor of adverse outcome after HSCT (Guardiola et al, Blood93, 1999: 2831; Deeg et al, Blood102, 2003: 3912). In our hands however, red cell transfusion dependence is the relevant cut off point for survival as pts with risk score 1 without need for transfusions had the same DFS as pts with risk score 0. Transfusion dependence may be a marker of disease progression and of increased toxicity at a time. AlloHSCT therefore should be performed earlier during the natural course of the disease, ie before transfusion dependence occurs, when DFS is excellent.

scholarly journals Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors effectively condition for allogeneic hematopoietic stem cell transplantation

2020 ◽  
Author(s):  
Stephen P. Persaud ◽  
Julie K. Ritchey ◽  
Jaebok Choi ◽  
Peter G. Ruminski ◽  
Matthew L. Cooper ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Janus Kinase ◽  
Hematopoietic Stem ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

ABSTRACTDespite the curative potential of hematopoietic stem cell transplantation (HSCT), transplant conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADC) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely involved syngeneic HSCT; however, for treatment of acute leukemias or tolerance induction for solid organ transplantation, strategies for allogeneic HSCT (allo-HSCT) are needed. Using murine allo-HSCT models, we show that combining CD45-targeted ADCs with the Janus kinase inhibitor baricitinib enables multilineage alloengraftment with >80-90% donor chimerism. Mechanistically, baricitinib impaired T and NK cell survival, proliferation and effector function, with NK cells being particularly susceptible due to inhibited IL-15 signaling. Unlike irradiated mice, CD45-ADC-conditioned mice did not manifest graft-versus-host alloreactivity when challenged with mismatched T cells. Our studies demonstrate novel allo-HSCT conditioning strategies that exemplify the promise of immunotherapy to improve the safe application of HSCT for treating hematologic diseases.

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