In vitro studies have demonstrated that Ki-PEG-CBZ is highly effective against ovarian cancer. We suggest that the developed polymer-drug nanoconjugate is an effective and safe nanoconjugate for the treatment of ovarian cancer.

To investigate the activity of CD117-ADC in non-human primates, we administered a single injection of ADC without HSC infusion, resulting in a >99% depletion of CD34+CD90+ bone marrow cells in cynomolgus macaques (n=2 of 3 in 0.1 mg/kg and n=3 in 0.3 mg/kg); similar to the ablation observed with 4 doses of myeloablative busulfan (Bu) (n=3). The transplanted animals with ADC maintained their fertility. Overall, these data indicate that an ADC-based targeted approach offers safer conditioning and could improve the risk-benefit profile in HSC gene therapy.

Objective: To reduce acute and long-term treatment-related toxicities, we have developed a first of its kind treatment intended to improve the safety of allo-HSCT through: 1) a TBI- and busulfan-free conditioning regimen consisting of briquilimab, rabbit ATG (rATG - Thymoglobulin), fludarabine, cyclophosphamide and rituximab - briquilimab (formerly called JSP191) is a monoclonal antibody (mAb) that targets human CD117 to deplete host HSCs enabling blood and immune reconstitution with minimal toxicity with the other agents being used for transient immune suppression to prevent immunologic rejection; 2) transplantation of TCRαβ+ T-cell/CD19+ B-cell hematopoietic grafts - a stem cell therapy that enhances donor hematopoietic and immune reconstitution while decreasing GvHD; and 3) a pre- and post-transplant monitoring protocol to maximize engraftment. All three patients in the Phase 1b portion of the study show early safety and efficacy of this approach. Briquilimab was well tolerated and all patients have shown prompt and durable donor engraftment. This data indicates that it might be possible to remove irradiation or alkylator chemotherapy from the conditioning regimen in patients with FA without matched sibling donors thus decreasing the chances for cancer predisposition in these patients that have inherited DNA repair defects.

P1/2, N=22, Terminated, Magenta Therapeutics, Inc. | N=55 --> 22 | Trial completion date: Oct 2023 --> Feb 2023 | Recruiting --> Terminated | Trial primary completion date: Oct 2023 --> Feb 2023; Sponsor Decision

Acute leukemia in Yemen was equally prevalent between adults and children with slightly more prevalent among males. Flow cytometry, even with a 3-colour strategy, is able to give useful diagnostic information about cell lineage of acute leukaemias. This has proven beneficial for patient management.

MGTA-117 has been well tolerated with no unexpected safety concerns. It has shown proof-of-mechanism (robust receptor binding, selective target cell depletion) and rapid clearance with in vivo stability. Further dose escalation continues, and progress is being made toward development of MGTA-117 to enable HSCT in AML/MDS and gene therapy indications.

MGTA-117 has been well tolerated with no unexpected safety concerns. Preliminary data show in vivo stability of the ADC with rapid clearance from blood, robust binding of MGTA-117 on CD117+ cells, and early evidence of single-agent biological activity. The observed PK/PD profile in humans is highly consistent with predictions based on data from studies in preclinical species.

Ultimately, GBM U87 cells assumed programmed cell death at a very low concentration due to nanocarrier-mediated drug delivery along with the chosen combination of drugs. Together, this study demonstrated the advantage of GO-PEG mediated combined delivery of CPI444 and vatalanib drugs with increased permeability, a three-pronged combinatorial strategy toward effective GBM treatment.

rhSCF is a convenient and effective vector for drug delivery to KIT positive GIST cells. SCF-DM1 is an effective drug candidate to treat imatinib-sensitive and -resistant GIST.

P1/2, N=55, Recruiting, Magenta Therapeutics, Inc. | N=42 --> 55

CD117 receptor occupancy by MGTA-117 will be measured and MSBE dose will be based on safety and receptor occupancy. The study is designed with the possibility that subjects would proceed to HSCT >28 days after MGTA-117 administration, if eligible per the local transplant practices.

Nivolumab therapy reduced the frequency of total peripheral ILCs but increased the percentage of CD117 ILC2s and enhanced the capability of ILC2s and CD117 ILCs to secrete IL-13 and TNFα, respectively...Moreover, melanoma cells boosted TNFα production in all ILC subsets and increased the number of IL-13 producing ILC2s in vitro. Our work shows for the first time that PD-1 blockade is able to affect ILCs proportions and functions in melanoma patients and that a specific subpopulation is associated with the therapy response.

Combination treatment with 4C9-DM1 plus carboplatin/etoposide or lurbinectedin resulted in a TGI rate greater than 90% compared with the vehicle control. Taken together, these results indicate that 4C9-DM1 is a potential therapeutic agent for SCLC treatment.

This linker-payload system is the same used in ado-trastuzumab emtansine, an approved ADC for HER2-positive breast cancer. There were no significant toxicities detected at doses up to 60 mg/kg in normal mice, suggesting a therapeutic index greater than 20 times. In conclusion, NN3201 showed potent anti-tumor activity and was selected as preclinical candidate.

While tyrosine kinase inhibitors such as imatinib are effective therapies for c-KIT mutant GIST, resistance often occurs by the development of secondary mutations in the intracellular signaling domains...ETB-drug conjugates (ETB-DCs) exhibited improved cytotoxicity in vitro, especially in CD117-low target cells. Moving forward, we plan to explore both the ETB and the ETB-DC therapeutic index in vivo with a series of CD117+ tumor efficacy and HSC depletion models.

P1/2, N=42, Recruiting, Magenta Therapeutics, Inc.

Treatment protocols evolved during GO utilization and these changes in practice patterns could have impacted clinical outcomes. Lastly, this study highlights the fact that patients with CBF AML can expect to have favorable outcomes.

We have generated a novel bispecific antibody, which binds to human CD117 (expressed on HSCPs and AML/MDS blast cells) and to CD3 (expressed on T cells), which we term CD117xCD3 TEA. The antibody induces selective T cell-mediated killing of cell lines with different surface levels of CD117, as well as of healthy HSPCs and primary human AML cells. Thus, the newly generated CD117xCD3 TEA might be developed clinically in order to erradicate residual AML/MDS and at the same time serve as a milder preconditioning approach prior to allo-HSCT in frail AML/MDS patients.

Conclusion Together, we show that MPN NSC reside in a CD34+/CD38− fraction of the malignant clone and display a unique phenotype, including immune checkpoint molecules, cytokine receptors and other target antigens. Our results should support the isolation of MPN NSC and the development of NSC-eradicating therapies in MPN.

We are currently exploring non-genotoxic host lymphocyte depletion to complement CD117-saporin conditioning to prevent lymphoid malignancy caused by residual Atm-/- T cells. Additionally, the role of donor myeloid derived microglial-like cell reconstitution in brain and its effects on decreasing neuroinflammation and neurodegeneration are being evaluated.

In the CD117-expressing Kasumi-1 cell line derived xenograft model (Figure 1C), MGTA-117, both as a single dose (3 & 10 mg/kg) and as a multi-dose (3 mg/kg QODx2), resulted in a 2.4-2.7-fold increase in median survival compared to vehicle (PBS), isotype-ADC, or standard of care (SOC) cytarabine (ARA-C, 30 mg/kg QDx5).  These data demonstrate that MGTA-117 has potential to be a potent targeted conditioning and anti-leukemia agent. Together with prior reports demonstrating MGTA-117 as an effective conditioning agent in an animal model, this targeted ADC approach has the potential to improve HSCT outcomes in AML by reducing leukemic burden peri-transplant and may decrease the toxicities associated with current conditioning regimens.

In the CD117-expressing Kasumi-1 cell line derived xenograft model (Figure 1C), MGTA-117, both as a single dose (3 & 10 mg/kg) and as a multi-dose (3 mg/kg QODx2), resulted in a 2.4-2.7-fold increase in median survival compared to vehicle (PBS), isotype-ADC, or standard of care (SOC) cytarabine (ARA-C, 30 mg/kg QDx5).  These data demonstrate that MGTA-117 has potential to be a potent targeted conditioning and anti-leukemia agent. Together with prior reports demonstrating MGTA-117 as an effective conditioning agent in an animal model, this targeted ADC approach has the potential to improve HSCT outcomes in AML by reducing leukemic burden peri-transplant and may decrease the toxicities associated with current conditioning regimens.

In the CD117-expressing Kasumi-1 cell line derived xenograft model (Figure 1C), MGTA-117, both as a single dose (3 & 10 mg/kg) and as a multi-dose (3 mg/kg QODx2), resulted in a 2.4-2.7-fold increase in median survival compared to vehicle (PBS), isotype-ADC, or standard of care (SOC) cytarabine (ARA-C, 30 mg/kg QDx5).  These data demonstrate that MGTA-117 has potential to be a potent targeted conditioning and anti-leukemia agent. Together with prior reports demonstrating MGTA-117 as an effective conditioning agent in an animal model, this targeted ADC approach has the potential to improve HSCT outcomes in AML by reducing leukemic burden peri-transplant and may decrease the toxicities associated with current conditioning regimens.

In the CD117-expressing Kasumi-1 cell line derived xenograft model (Figure 1C), MGTA-117, both as a single dose (3 & 10 mg/kg) and as a multi-dose (3 mg/kg QODx2), resulted in a 2.4-2.7-fold increase in median survival compared to vehicle (PBS), isotype-ADC, or standard of care (SOC) cytarabine (ARA-C, 30 mg/kg QDx5).  These data demonstrate that MGTA-117 has potential to be a potent targeted conditioning and anti-leukemia agent. Together with prior reports demonstrating MGTA-117 as an effective conditioning agent in an animal model, this targeted ADC approach has the potential to improve HSCT outcomes in AML by reducing leukemic burden peri-transplant and may decrease the toxicities associated with current conditioning regimens.

GVHD prophylaxis included tacrolimus, sirolimus, and mycophenolate mofetil... These early results are the first to demonstrate that JSP191/TBI/Flu is safe, well-tolerated, and capable of clearing MDS/AML MRD in older adults undergoing NMA AHCT. Accrual onto this study is continuing. Correlative analyses demonstrating the impact of JSP191 on HSCs are ongoing and will be presented at the meeting.

GVHD prophylaxis included tacrolimus, sirolimus, and mycophenolate mofetil... These early results are the first to demonstrate that JSP191/TBI/Flu is safe, well-tolerated, and capable of clearing MDS/AML MRD in older adults undergoing NMA AHCT. Accrual onto this study is continuing. Correlative analyses demonstrating the impact of JSP191 on HSCs are ongoing and will be presented at the meeting.

GVHD prophylaxis included tacrolimus, sirolimus, and mycophenolate mofetil... These early results are the first to demonstrate that JSP191/TBI/Flu is safe, well-tolerated, and capable of clearing MDS/AML MRD in older adults undergoing NMA AHCT. Accrual onto this study is continuing. Correlative analyses demonstrating the impact of JSP191 on HSCs are ongoing and will be presented at the meeting.

GVHD prophylaxis included tacrolimus, sirolimus, and mycophenolate mofetil... These early results are the first to demonstrate that JSP191/TBI/Flu is safe, well-tolerated, and capable of clearing MDS/AML MRD in older adults undergoing NMA AHCT. Accrual onto this study is continuing. Correlative analyses demonstrating the impact of JSP191 on HSCs are ongoing and will be presented at the meeting.

GVHD prophylaxis included tacrolimus, sirolimus, and mycophenolate mofetil... These early results are the first to demonstrate that JSP191/TBI/Flu is safe, well-tolerated, and capable of clearing MDS/AML MRD in older adults undergoing NMA AHCT. Accrual onto this study is continuing. Correlative analyses demonstrating the impact of JSP191 on HSCs are ongoing and will be presented at the meeting.

Antibody-drug conjugates, bispecific T-cell engaging and activating antibodies (TEA) or CAR T-cells might offer increased efficacy compared to naked antibodies and yet higher tolerability and safety compared to current genotoxic conditioning approaches. Here, we summarize the current state regarding immunological conditioning concepts for the treatment of HSC disorders and outline potential future developments.

Future expansion of this methodology into other cellular therapies (CAR NK or BiTE) and the examination of new data sources could reveal additional targets with robust expression in AML. Demonstration of cell surface expression of these targets, and appropriate preclinical evidence of efficacy, could lay the groundwork for quickly moving these therapies to clinical trials in AML.

Moreover, antibody-mediated immunological targeting through CD33 or CD52 resulted in LSC depletion in vitro and a substantially reduced LSC engraftment in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Together, we have established surface marker and target expression profiles of AML LSCs and CML LSCs, which should facilitate LSC enrichment, diagnostic LSC phenotyping, and development of LSC-eradicating immunotherapies.