Thrombopoietin receptor agonist antibody for treating chemotherapy-induced thrombocytopenia

• Published in: BMC cancer Vol. 23; no. 1; p. 490
• Main Authors: Shin, Jiwon, Kim, Min-Jung, Quan, Xingguo, Kim, Ji Woong, Lee, Sukmook, Park, SaeGwang, Jeong, Jee-Yeong, Yea, Kyungmoo
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 31-05-2023; BioMed Central; BMC
• Subjects: 5-Fluorouracil; Agonist antibody; Agonists; Animals; Antibodies; Antigens, CD34; Antineoplastic Agents - adverse effects; Apheresis; Blood platelets; Blood Platelets - metabolism; Cancer; CD34 antigen; Cell differentiation; Cell growth; Cell proliferation; Chemotherapy; Chemotherapy-induced thrombocytopenia; Complications and side effects; Drug dosages; Female; Flow cytometry; Fluorouracil - therapeutic use; Humans; Injection; Kinases; Leukemia; Libraries; Megakaryocytes; Megakaryopoiesis; Mice; Peripheral blood; Phage display; Platelet production; Platelets; Ploidy; Prevention; Proteins; R&D; Receptors, Thrombopoietin; Recombinant Proteins - adverse effects; Research & development; Risk factors; Testing; Thrombocytopenia; Thrombocytopenia - chemically induced; Thrombocytopenia - drug therapy; Thrombopoiesis; Thrombopoietin; Thrombopoietin receptor; Viral antibodies; South Korea; Minneapolis Minnesota; United States > US; Agonist antibody; Platelet production; Thrombopoietin receptor; Chemotherapy-induced thrombocytopenia; Megakaryopoiesis
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-023-10975-3

Thrombocytopenia is a common complication in cancer patients undergoing chemotherapy. Chemotherapy-induced thrombocytopenia (CIT) leads to dose reduction and treatment delays, lowering chemotherapy efficacy and survival rate. Thus, rapid recovery and continuous maintenance of platelet count during chemotherapy cycles are crucial in patients with CIT. Thrombopoietin (TPO) and its receptor, myeloid proliferative leukemia (MPL) protein, play a major role in platelet production. Although several MPL agonists have been developed to regulate thrombopoiesis, none have been approved for the management of CIT due to concerns regarding efficacy or safety. Therefore, the development of effective MPL agonists for treating CIT needs to be further expanded.
Anti-MPL antibodies were selected from the human combinatorial antibody phage libraries using phage display. We identified 2R13 as the most active clone among the binding antibodies via cell proliferation assay using BaF3/MPL cells. The effect of 2R13 on megakaryocyte differentiation was evaluated in peripheral blood CD34
cells by analyzing megakaryocyte-specific differentiation markers (CD41a
and CD42b
) and DNA ploidy using flow cytometry. The 2R13-induced platelet production was examined in 8- to 10-week-old wild-type BALB/c female mice and a thrombocytopenia mouse model established by intraperitoneal injection of 5-fluorouracil (150 mg/kg). The platelet counts were monitored twice a week over 14 days post-initiation of treatment with a single injection of 2R13, or recombinant human TPO (rhTPO) for seven consecutive days.
We found that 2R13 specifically interacted with MPL and activated its signaling pathways. 2R13 stimulated megakaryocyte differentiation, evidenced by increasing the proportion of high-ploidy (≥ 8N) megakaryocytes in peripheral blood-CD34
cells. The platelet count was increased by a single injection of 2R13 for up to 14 days. Injection of 5-fluorouracil considerably reduced the platelet count by day 4, which was recovered by 2R13. The platelets produced by 2R13 sustained a higher count than that achieved using seven consecutive injections of rhTPO.
Our findings suggest that 2R13 is a promising therapeutic agent for CIT treatment.