 Juan Carlos Lopez |
 Andy Marshall |
The Summer BIO report “The State of Emerging Biotech Companies: Investment, Deal, and Pipeline Trends” highlights how much China-based programs have contributed to the drug pipeline over the past 10 years.
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A couple of weeks ago, Bloomberg also summarized deal data showing how the share of global licensing by Chinese biotech companies has jumped over the past two years.
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Judging by a report listing 16 ‘high-value’ currently unlicensed assets from China being hawked by longtime Phalanx Investment Partners analyst David Maris, there is more licensing to come.
In this context, we read with interest a recent Science Immunology paper describing a monoclonal antibody (mAb) program targeting a novel phagocytic checkpoint under development at yet another Chinese biotech: MedimScience, founded in Hangzhou City in 2021. MedimScience is one of a growing cadre of companies, including LTZ Therapeutics, Dren Bio, Chengdu Kanghong, Antengene and ImmuneOnco, looking to develop novel myeloid cell engagers/phagocytic checkpoint inhibitors.
Phagocytic checkpoint inhibitors are drugs that circumvent the molecular cloaks that tumors throw around themselves to avoid uptake and destruction by myeloid cells, such as macrophages, monocytes, and neutrophils. The strategy first came to the fore through pioneering work on the ‘don’t eat me’ signal CD47, work carried out by Ravi Majeti and Irv Weissman at Stanford. Results from their preclinical studies spurred the launch of startup Forty Seven (subsequently acquired in 2020 by Gilead) and the first-in-class anti-CD47 IgG4 magrolimabprogram.Phase 1b trial results of magrolimab combined with azacitidine in acute myeloid leukemia (AML) patients were so impressive that, by 2022, more than 20 different companies had anti-CD47 programs in clinical development. This blew up spectacularly when early trials failed to be reproduced in larger efficacy trials of combinations — failure that was largely attributed to intolerability/anemia issues related to the target, slow action/early disease progression, and a failure to account for patient heterogeneity with regard to P53 mutation status. But the strategy is compelling and the hunt for new phagocytic checkpoints has continued with new antibody formats seeking to avoid these pitfalls.
Now, Cheng Zhong and his colleagues at MedimScience report the identification of a new evasion actor — PSGL-1 — that suppresses macrophage-mediated phagocytosis in a variety of hematological malignancies. PSGL-1, which was previously known largely for its role in cell adhesion, is highly expressed in various hematologic cancers, including AML, T-acute lymphoblastic leukemia (T-ALL) and multiple myeloma (MM).
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Moreover, high PSGL-1 expression has been found to correlate with poor patient survival in AML, T-ALL and MM.
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Using several mouse models, the researchers found that tumors lacking PSGL-1 show slower progression, increased macrophage infiltration, and higher rates of phagocytosis by macrophages, effects that were independent of T cells or dendritic cells.
Mechanistically, the team found that PSGL-1 disrupts the interaction between the cell-adhesion molecule ICAM-1 on tumor cells and the integrin LFA-1 (CD11a/CD18) on macrophages. And when they tested Novartis’ lifitegrast, an inhibitor of ICAM-1/LFA-1 binding, they found this largely abrogates the phagocytosis of PSGL-1 knockout tumor cells, confirming PSGL1’s role in impairing prophagocytic signaling and cytoskeletal reorganization required for effective tumor-cell engulfment.
The authors went on to develop a humanized mAb against PSGL-1 and show its ability to induce phagocytosis of human tumor cells in vitro and to reduce tumor burden in mouse models of AML, T-ALL, and MM. The antibody showed a good safety profile in non-human primates with no significant toxicity at high doses. Additionally, PSGL-1 blockade synergized with chemotherapy (doxorubicin) and antibody-based therapies (anti-CD47 and anti-CD38), further underscoring the translational potential of this strategy, particularly in treatment-resistant settings.
