Identification of Candidate Target Antigens for Antibody-Based Immunotherapy in Childhood B-Cell Precursor ALL

Abstract

Background: Contemporary risk adapted treatment protocols for childhood acute lymphoblastic leukemia (ALL) rely on accurate risk assessment strategies for disease reoccurrence by incorporating clinical parameters as well as immunological, molecular and cytogenetic features of the blasts at initial manifestation. Additional risk stratification is provided by analysis of the in vitro and in vivo response of the blasts towards standard chemotherapy. Despite adapted therapies, a number of children with good and bad prognostic factors still fail therapy. One approach to this problem might be to incorporate monoclonal antibodies (MoAbs) as additional modalities into the first or second line treatment. Patients and Methods: In order to identify target antigen structures, we analyzed the immunological expression profiles of blasts from 181 patients with B-cell precursor ALL treated at our institution in 11 years according to the CoALL-92/97/03 protocols. Blasts were classified according to the EGIL guidelines as 9 proB-, 110 common (c-) and 62 preB-ALL. Results: > 99 and 96 % of patients expressed CD19 and CD22 on > 90 % of their blasts, respectively. HLA-DR on > 95 % blasts was present in all patients. CD10 was expressed on all c-/preB-ALL and absent on proB-ALL cells. CD20 was expressed on 11-37 % of B-cell precursor ALL samples. CD34 positive blasts were found in 89, 83 and 68 % of patients with proB-, c- and preB-ALL, respectively. CD37 expression was detected in 0-18 % of patients. < 20 % CD45+ blasts were found in 11, 19 and 18 % of patients with proB-, c- and preB-ALL. CD33+ was expressed on 33, 29 and 21 % of patients samples with proB-, c- and preB-ALL. Other myeloid antigens (CD13, CD14, CD15, CD65) were positive on blasts in < 25 % of patients. Analyses of the immunological profile of blasts in 9 consecutive children with relapse revealed that the antigen expression profile varied little compared to the initial diagnosis for CD10, CD19, CD22 and HLA-DR. Conclusions: These analyses clearly identified the three antigens CD19, CD22 and HLA-DR present on blasts in more than 90 % of patients as potential target structures for targeted therapies with native or toxin-bound monoclonal antibodies in childhood ALL.

Zusammenfassung

Hintergrund: Gegenwärtige Risiko-adaptierte Behandlungsprotokolle für Kinder und Jugendliche mit akuter lymphoblastischer Leukämie (ALL) basieren auf akkuraten Risikoabschätzungsstrategien für das Auftreten eines Rezidives, denen klinische Parameter, immunologische, molekularbiologische und zytogenetische Eigenschaften der Blasten zum Diagnosezeitpunkt zugrunde liegen. Eine zusätzliche Risikostratifizierung erfolgt durch das In-vitro- oder In-vivo- Ansprechen der Blasten auf eine Standardchemotherapie. Trotz entsprechend durchgeführter Therapien erleiden eine Anzahl an Kindern mit guten und schlechten prognostischen Merkmalen ein Rezidiv. Eine Verbesserung der Prognose könnte durch den Einsatz monoklonaler Antikörper als zusätzliche Behandlungsmodalität in der Primär- oder Sekundärtherapie erreicht werden. Patienten und Methodik: Um potenzielle Zielstrukturen für monoklonale Antikörper zu identifizieren, untersuchten wir das immunologische Expressionsprofil der Blasten von 181 Patienten mit B-Zell-Vorläufer-ALL, welche in den vergangenen 11 Jahren in unserer Klinik nach den CoALL-Protokollen 92/97/03 behandelt wurden. Die Blasten wurden gemäß den EGIL-Kriterien als 9 proB-, 110 common (c-) und 62 präB-ALL klassifiziert. Ergebnisse: > 99 bzw. 96 % der Patienten exprimieren CD19 bzw. CD22 auf > 90 % der Blasten. HLA-DR war bei allen Patienten auf > 95 % der Blasten vorhanden. CD10 wurde auf allen c-/präB-ALL exprimiert und fehlte auf den proB-ALL Blasten. CD20 war auf 11-37 % der B-Vorläufer-ALL-Proben nachweisbar. CD34-positive Blasten wurden bei jeweils 89, 83 und 68 % der Patienten mit proB-, c- und präB-ALL gefunden. Eine Expression von CD37 auf den Blasten konnte in 0-18 % der Patienten nachgewiesen werden. < 20 % CD45+ Blasten waren bei 11, 19 und 18 % der Patienten mit proB-, c- und präB-ALL nachweisbar. CD33 war auf jeweils 33, 29 und 21 % der proB-, c- und präB-ALL Proben nachweisbar. Andere myeloische Antigene (CD13, CD14, CD15, CD65) waren bei < 25 % der Patienten auf den Blasten exprimiert. Analysen des immunologischen Antigenprofils der Blasten zum Zeitpunkt der Diagnose und des Rezidives bei 9 konsekutiven Patienten zeigte hinsichtlich der Expression von CD10, CD19, CD22 und HLA-DR wenig Unterschiede. Schlussfolgerungen: Diese Analysen identifizieren die drei Antigene CD19, CD22 und HLA-DR, die auf den Blasten von mehr als 90 % der Patienten nachweisbar sind, als mögliche Zielstrukturen für den Einsatz von nativen oder Toxin-gebundenen monoklonalen Antikörpern bei Kindern und Jugendlichen mit ALL.

Key words

Childhood ALL - Immunophenotyping - targeted therapies - monoclonal antibodies

Schlüsselwörter

ALL bei Kindern und Jugendlichen - Immunphänotyp - „targeted therapy” - monoklonale Antikörper

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