Magenta Therapeutics Presents Preclinical Data on Targeted Non-Genotoxic Conditioning Programs Demonstrating Potent Stem Cell Depletion and Anti-Leukemia Survival Benefit

(NASDAQ:MGTA), a clinical-stage biotechnology company
developing novel medicines to bring the curative power of bone marrow
transplant to more patients, today announced that the Company presented
preclinical research on its targeted conditioning programs at the 60th
annual meeting of the American Society of Hematology (ASH).

Patients undergoing bone marrow transplant or stem cell gene therapy are
first prepared, or conditioned, with non-specific, genotoxic
chemotherapy alone or in combination with total body irradiation. This
conditioning process is associated with significant toxicity, including
development of cancers, infertility, organ toxicities, or even death. As
a result, many patients do not consider undergoing a bone marrow
transplant or gene therapy. Magenta is developing a portfolio of
targeted antibody drug conjugates (ADCs), including non-genotoxic
agents, that selectively remove the specific cells to enable a
successful transplant or gene therapy procedure.

“This year’s five ASH data presentations from our portfolio of targeted
conditioning programs give further insight into our progress in
addressing one of the major challenges of the transplant and gene
therapy process: the genotoxic conditioning that leaves patients
infertile and puts them at risk for malignancies and organ toxicity,”
said Michael Cooke, Ph.D., chief scientific officer, Magenta
Therapeutics. “Our most advanced targeted conditioning program, C200, is
focused on ADCs directed at CD117, a target expressed on stem cells and
many types of leukemia cells. Preclinical data at ASH this year show
potent and selective depletion of human and non-human primate stem cells
with our non-genotoxic CD117 ADC conjugated to amanitin. In addition,
both this ADC and our CD45-targeted ADC from our C100 program
demonstrated the additional benefit of anti-leukemia activity and
survival advantage in patient-derived leukemia models. Based on these
promising data, we are finalizing the CD117 and CD45 ADCs, and we expect
to select a lead for development for the CD117 program to launch
IND-enabling studies in 2019.”

CD117-Amanitin Antibody Drug Conjugates Effectively Deplete Human
and Non-Human Primate HSCs: Proof of Concept as a Targeted Strategy for
Conditioning Patients for Bone Marrow Transplant, Abstract #3314

Key results, presented by Brad Pearse, Ph.D., Magenta Therapeutics:

  • An anti-CD117 ADC conjugated with amanitin potently depleted human and
    non-human primate hematopoietic stem cells and progenitors in vivo.
  • An anti-CD117 amanitin ADC with engineered fast half-life showed
    potent stem cell depletion and rapid clearance, providing appropriate
    pharmacokinetics for patient preparation for bone marrow transplant.
  • The ADCs were well tolerated at the efficacious doses.
  • Potent and selective depletion of stem cells with rapid clearance of
    the ADC could provide a significant improvement over current
    approaches to patient preparation with an acceptable safety profile
    prior to BMT for malignancies, autoimmune diseases and gene therapies,
    broadening patient access to these potentially curative therapies.
  • Magenta will next finalize the linker-toxin construct and select a
    lead for development in 2018, then begin IND-enabling studies in 2019.

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, Abstract #3316

Key results, presented by Jennifer Proctor, Magenta Therapeutics:

  • CD117 is expressed on human hematopoietic stem and progenitor cells
    and on leukemia cells in 80% of patients with acute myeloid leukemia
    (AML) and in 65% of patients with myelodysplastic syndromes (MDS);
    CD45 is expressed on all lympho-hematopoietic cells and in nearly all
    blood cancers, other than multiple myeloma.
  • Both the anti-CD117 amanitin ADC (C200 program) and the anti-CD45
    amanitin ADC (C100 program) showed potent killing of human
    hematopoietic stem cells and human leukemia cell lines expressing
    these targets in vitro.
  • A single dose of either ADC showed potent in vivo anti-leukemia
    activity in mice bearing established human leukemia cell lines.
  • Both ADCs also significantly improved the survival of mice engrafted
    with human leukemia cells from AML patients, including leukemias that
    were resistant to multiple lines of therapy including previous
    allogeneic bone marrow transplant.
  • Magenta Therapeutics’ C200 and C100 programs are designed with the
    dual intent of selectively eliminating the necessary cells to enable a
    successful transplant and reducing disease burden in patients with
    active disease or in patients who are at high risk of disease relapse.
  • Magenta will next finalize the linker-toxin constructs, select
    anti-CD117 and anti-CD45 leads for development and continue to
    progress ADC-based conditioning approaches targeting CD45 and CD117
    toward clinical development.

Antibody Drug Conjugates Targeted to CD45 or CD117 Enable
Allogeneic Hematopoietic Stem Cell Transplantation in Animal Models,
Abstract #3324

Key results, presented by Sharon Hyzy, M.S., Magenta Therapeutics:

  • ADCs targeted to mouse CD45 or mouse CD117 have been shown to
    effectively condition immunocompetent mice for autologous bone marrow
  • To investigate the utility of these murine-specific tool ADCs
    conjugated to saporin to enable allogenic transplant, Magenta assessed
    these ADCs as single agents or in combination with immunosuppressive
    agents to facilitate transplant in a murine allogeneic transplant
  • Both anti-CD45 and anti-CD117 saporin ADCs, when combined with
    additional immunosuppressants, enabled successful minor mismatch whole
    bone marrow transplants in mouse models.
  • Conditioning with the anti-CD45 saporin ADC plus post-transplant
    cyclophosphamide to prevent graft vs. host disease enabled successful
    engraftment across minor histocompatibility antigens.
  • The ADCs were more effective than an unconjugated anti-CD45 antibody,
    pre-transplant cyclophosphamide, or sublethal irradiation in
    combination with post-transplant cyclophosphamide.
  • Magenta will next investigate other linker-toxins as well as ADC-based
    conditioning in various allogeneic mouse models.

Non-genotoxic conditioning facilitates robust HSPC engraftment and
multi-lineage development in a dose dependent manner in Fanconi anemia,
Abstract #2041

Key results, presented by Meera Srikanthan, Ph.D., Fred Hutchinson
Cancer Research Center:

  • Conditioning with genotoxic chemotherapy in patients with Fanconi
    anemia is currently utilized to open the bone marrow niche prior to
    infusion of hematopoietic stem cells in a bone marrow transplant but
    is often associated with genotoxic effects.
  • ADCs targeting hematopoietic stem cells are an emerging non-genotoxic
    method of conditioning, particularly in diseases associated with DNA
    damage and cancer predisposition, such as Fanconi anemia.
  • Researchers at the Fred Hutchinson Cancer Research Center sought to
    study the application of non-genotoxic ADC-based conditioning
    targeting hematopoietic stem cells to eliminate leukemogenic host HSCs
    and to facilitate the engraftment of donor cells.
  • Results showed that the immunotoxin-based conditioning drugs from
    Magenta are of similar if not superior efficacy compared to
    cyclophosphamide, facilitating multi-lineage engraftment of autologous
    stem cells, as would be used in gene therapy.
  • Researchers at the Fred Hutchinson Cancer Research Center will next
    determine whether immunotoxin conditioning facilitates engraftment of
    gene-modified stem cells using FancA (-/-) mice and optimize dosing of
    immunotoxin platform to completely eliminate host hematopoiesis in
    order to decrease the risk of leukemogenesis.

Targeting CD45 with an Amanitin Antibody-Drug Conjugate
Effectively Depletes Human HSCs and Immune Cells for Transplant
Conditioning, Abstract #4526

Key results will be presented by Rahul Palchaudhuri, Ph.D., Magenta
Therapeutics, on Monday, December 3, 2018.

  • A human/primate cross-reactive anti-CD45 amanitin ADC potently
    depletes human hematopoietic stem cells and immune cells in culture.
  • The anti-CD45 ADC achieved efficient depletion of immune cells in the
    periphery and hematopoietic stem cells in the bone marrow of humanized
  • Simultaneous depletion of immune and hematopoietic stem cells using an
    anti-CD45 ADC may enable safer conditioning for allogeneic transplant
    and enable immune-reset in autoimmune disease transplantation.
  • Magenta plans to optimize the anti-CD45 ADC and select a development
    candidate in 2019, with IND-enabling studies to begin in 2020.

About Magenta Therapeutics

Headquartered in Cambridge, Mass., Magenta Therapeutics is a
clinical-stage biotechnology company developing novel
medicines for patients
with autoimmune diseases, blood cancers
and genetic diseases. By creating a platform focused on critical areas
of unmet need, Magenta Therapeutics is pioneering an integrated approach
to allow more patients to receive one-time, curative therapies by making
the process more effective, safer and easier.

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