Abrogation of the Hematological and Biological Activities of the Interleukin-3/Granulocyte-Macrophage Colony-Stimulating Factor Fusion Protein PIXY321 by Neutralizing Anti-PIXY321 Antibodies in Cancer Patients Receiving High-Dose Carboplatin

• Published in: Blood Vol. 93; no. 10; pp. 3250 - 3258
• Main Authors: Miller, Langdon L., Korn, Edward L., Stevens, Diane S., Janik, John E., Gause, Barry L., Kopp, William C., Holmlund, Jon T., Curti, Brendan D., Sznol, Mario, Smith, John W., Urba, Walter J., Donegan, Sarah E., Watson, Thelma M., Longo, Dan L.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-05-1999; The Americain Society of Hematology
• Subjects: Adult; Antibody Formation; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Carboplatin - adverse effects; Carboplatin - therapeutic use; Cholesterol - blood; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Granulocyte-Macrophage Colony-Stimulating Factor - adverse effects; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacokinetics; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; Humans; Interleukin-3 - adverse effects; Interleukin-3 - immunology; Interleukin-3 - pharmacokinetics; Interleukin-3 - therapeutic use; Leukocyte Count - drug effects; Medical sciences; Neoplasms - drug therapy; Pharmacology. Drug treatments; Platelet Count - drug effects; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - pharmacokinetics; Recombinant Fusion Proteins - therapeutic use; Antineoplastic agent; Human; Toxicity; Cytokine; Malignant tumor; Biological activity; Chemotherapy; Treatment; Immunogenicity; Hematopoiesis; Interleukin 3; Immunotherapy; Myelosuppression; Fusion protein; Granulocyte macrophage colony stimulating factor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V93.10.3250.410k35_3250_3258

This dose-escalation study was performed to evaluate the hematologic activity, biological effects, immunogenicity, and toxicity of PIXY321 (an interleukin-3/granulocyte-macrophage colony-stimulating factor fusion protein) administered after high-dose carboplatin (CBDCA) treatment. Patients with advanced cancers received CBDCA at 800 mg/m2 intravenously on day 0 of repeated 28-day cycles. In part A of the study, patients were treated with CBDCA alone during cycle 1 and then received PIXY321 on days 1 through 18 of cycle 2 and later cycles. In part B, patients received 18 days of PIXY321 beginning on day 1 of all CBDCA cycles, including cycle 1. PIXY321 was administered subcutaneously in 2 divided doses. Total doses of 135, 250, 500, 750, and 1,000 μg/m2/d were administered to successive cohorts of 3 to 6 patients in part A. In part B, patient groups received PIXY321 doses of 750, 1,000, and 1,250 μg/m2/d. The hematologic effects of PIXY321 were assessed in the first 2 cycles of therapy. Anti-PIXY321 antibody formation was assessed by enzyme-linked immunosorbent assay (ELISA) and neutralization assay. Of the 49 patients enrolled, 31 were fully evaluable for hematologic efficacy. When comparing the first B cycle (cycle B-1; with PIXY321) with the first A cycle (cycle A-1; without PIXY321), the fusion protein had no significant effect on platelet nadirs or duration of platelets less than 20,000/μL but was able to speed the time of recovery of platelet counts to 100,000/μL (15v 20 days; P = .01). Significant improvements in neutrophil nadir and duration of ANC less than 500 were observed in cycles A-2 and B-1 (with PIXY321) as compared with cycle A-1 (without PIXY321). Initial PIXY321 prophylaxis (cycle A-2 and cycle B-1), enhanced the recovery of ANC to greater than 1,500/μL by an average of at least 8 days as compared with cycle A-1 (without PIXY321;P ≤ .004). However, positive PIXY321 hematologic effects were lost in the second course of PIXY321 among patients treated in part B. ELISA analysis showed that 92% of patients had developed neutralizing anti-PIXY321 antibodies by the completion of 2 PIXY321-containing cycles. The incidental action of PIXY321 to depress serum cholesterol levels was also abrogated during cycle B-2. We conclude that PIXY321 was active in speeding hematologic recovery but that neutralizing anti-PIXY321 antibody formation suppressed the hematologic and biochemical effects by the second cycle of PIXY321 administration. The immunogenicity of this fusion protein provides a cautionary warning that clinical development of bioengineered human molecules requires thorough testing for immune neutralization.