Details

Autor(en) / Beteiligte

• Proctor, Jennifer L.
• Hyzy, Sharon L.
• Adams, Hillary L.
• Brooks, Melissa
• Gabros, Andrew D.
• McDonough, Sean M.
• Kien, Lena
• Aslanian, Sharon
• Pearse, Bradley R.
• Palchaudhuri, Rahul
• Li, Qing
• Sarma, Ganapathy N.
• Ladwig, Danielle
• Dushime, Junia
• Panwar, Rajiv
• McDonagh, Charlotte F.
• Boitano, Anthony E.
• Cooke, Michael P.

Titel

Single Doses of Antibody Drug Conjugates (ADCs) Targeted to CD117 or CD45 Have Potent In Vivo Anti-Leukemia Activity and Survival Benefit in Patient Derived AML Models

Ist Teil von

• Biology of blood and marrow transplantation, 2019-03, Vol.25 (3), p.S100-S100

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2019

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Allogeneic bone marrow transplant (BMT) is a potentially curative approach in patients with refractory or high-risk hematologic malignancies, like acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Current regimens for patient preparation, or conditioning, prior to BMT limit the use of this procedure due to regimen-related mortality and morbidities. As a result, many eligible patients do not consider transplant and only 2/3 those transplanted are able to tolerate a reduced intensity conditioning regimen, which is associated with increased relapse (Scott, J Clin Onc 2017). Thus, safer and more effective conditioning agents with improved disease control are urgently needed. We developed two novel antibody drug conjugates (ADCs) conjugated to amanitin (AM) targeting CD117 (C-KIT, Pearse 2018), which is expressed on hematopoietic stem, progenitor, AML and MDS cells in >60% of patients (Ludwig, Haematologica 1997). CD45 (Palchaudhuri 2018) is expressed on all lympho-hematopoietic cells and hematologic malignancies except multiple myeloma. We aim to design ADC-based conditioning agents with the dual benefit of specifically depleting primary human hematopoietic stem progenitor cells (HSPCs) to enable BMT while reducing disease burden in leukemia models. ADCs were tested in xenograft murine models inoculated with human AML cells from immortalized cell lines (Kasumi-1, CD117 expressing leukemia; REH-Luc, CD45 expressing AML), and three AML patient-derived xenografts (PDX) expressing both CD117 and CD45 (2 of 3 are from patients that relapsed post allogeneic BMT). In the Kasumi model, a single dose of 0.3 mg/kg anti-CD117-AM on day 7 or 42 after inoculation markedly increased survival (median >240 days) compared to vehicle (median 76 days) or unconjugated anti-CD117 antibody (median 86.5 days) (n=6-8/group, p<0.01). In the REH-Luc model, a single dose of 1 mg/kg anti-CD45-AM on day 5 after inoculation increased median survival by 15 days compared to vehicle or unconjugated anti-CD45 antibody (n=10/group, p<0.01). In the PDX models, a single dose of ADCs (anti-CD117-AM, anti-CD45-AM, isotype-AM (ISO-AM), unconjugated anti-CD117 antibody, or vehicle PBS) was administered when 2-5% blasts were observed in the blood (n=4-5/group). Survival was significantly increased with 1 mg/kg anti-CD117-AM and 1 mg/kg anti-CD45-AM as compared to vehicle (Figure 1 and Table 1). Anti-CD117-AM and anti-CD45-AM are potent anti-leukemia agents based on these data in humanized murine models with established AML. Together with prior reports on the potency of anti-CD117-AM and anti-CD45-AM as conditioning agents, these non-genotoxic ADCs may be useful in reducing disease burden in patients and in recipients of reduced-dose conditioning who are at high risk of disease relapse.