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

Asim Saha, Sharon Hyzy, Tahirih Lamothe, Katelyn Hammond, Nicholas Clark, Leanne Lanieri, Prashant Bhattarai, Rahul Palchaudhuri, Geoffrey O. Gillard, Jennifer Proctor, Megan J. Riddle, Angela Panoskaltsis-Mortari, Margaret L. MacMillan, John E. Wagner, Hans Peter Kiem, Lisa M. Olson, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment of patients with nonmalignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current systemic nontargeted conditioning regimens mediate tissue injury and potentially incite and amplify GVHD, limiting the use of this potentially curative treatment beyond malignant disorders. Minimizing systemic nontargeted 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. We report an anti-mouse CD45-targeted-ADC (CD45-ADC) that facilitates stable murine multilineage donor cell engraftment. Conditioning with CD45-ADC (3 mg/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, pretransplant CD45-ADC (3 mg/kg) combined with low-dose TBI (150 cGy) 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 pretransplant TBI (50 cGy) and posttransplant rapamycin, cyclophosphamide (Cytoxan), or a JAK inhibitor, 90% to 100% of recipients achieved stable chimerism (mean: 77%, 59%, 78%, respectively). At a higher dose (5 mg/kg), CD45-ADC as a single agent was sufficient for rapid, high-level multilineage chimerism sustained through the 22 weeks observation period. Therefore, CD45-ADC has the 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.

Original languageEnglish (US)
Pages (from-to)1743-1759
Number of pages17
JournalBlood
Volume139
Issue number11
DOIs
StatePublished - Mar 17 2022

Bibliographical note

Funding Information:
This work was supported in part by National Institutes of Health grants R01 HL147324 and R37 AI34495 and Kids' First Fund (to B.R.B.).

Funding Information:
Conflict-of-interest disclosure: B.R.B. receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics, research funding from BlueRock Therapeutics, Rheos Medicines, Childrens' Cancer Research Fund, and Kids' First Fund, and is a cofounder of Tmunity Therapeutics. J.E.W. was an advisor at Magenta Therapeutics. S.H., T.L., K.H., N.C., L.L., P.B., R.P., G.O.G., J.P., and L.M.O. were employees and equity holders of Magenta Therapeutics at the time the work was completed.

Publisher Copyright:
© 2022 American Society of Hematology

Keywords

  • Animals
  • Chimerism
  • Graft vs Host Disease
  • Hematopoietic Stem Cell Transplantation/adverse effects
  • Immunoconjugates/pharmacology
  • Mice
  • Transplantation Conditioning/methods

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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