Simultaneous study of five candidate target antigens (CD20, CD22, CD33, CD52, HER2) for antibody-based immunotherapy in B-ALL: a monocentric study of 44 cases

In the last few years, targeted immunotherapy for haematological diseases has been developed to reduce the toxicity of chemotherapy and to improve treatment efficacy.1 As the prognosis of B-acute lymphoblastic leukaemia (B-ALL) in adults and in some children remains poor, we have investigated the simultaneous expression of five target surface antigens (sAg) (CD20, CD22, CD33, CD52, HER2) for which monoclonal antibodies are currently available for immunotherapy (rituximab, epratuzumab, gemtuzumab, alemtuzumab, trastuzumab).

We have identified a series of 44 B-ALL (22 males and 22 females) at diagnosis (n=40) or at relapse (n=4) between March 2000 and June 2008. The median age was 51 (range 5–92) years. There were 13 Philadelphia positive B-ALL. CD20, CD22, CD33, CD52 and HER2 expression was assessed using multicolour flow cytometry with the following phycoerythrin-conjugated monoclonal antibodies directed against: CD20 (L27), CD22 (SHCL1), CD33 (P67.6), HER2 (Neu 24.7) purchased from BD (San Jose, CA, USA) and CD52 (CF1.D12) purchased from Caltag (Buckingham, UK). A CD19+CD45+low blast cell gating strategy was also used. The mean fluorescence intensity ratio was obtained by dividing the mean fluorescence intensity of the considered antibody by that of its isotypic control. Positivity threshold was defined by a ratio intensity of 2.

When considering positivity in >30% of the blast population, CD20, CD22, CD33, CD52 and HER2 expression was observed in 29.5, 98, 54.5, 88.5 and 20.5% of patients, respectively. Of note, all patients were positive for at least one target surface antigen. In all, 2 (4%), 11 (25%), 23 (52%), 5 (11%) and 3 (7%) patients were positive for one, two, three, four or all five target sAg. The observed sAg combinations were as follows: one sAg (CD22, n=2); two sAg (CD22/CD52, n=8; CD22/CD33, n=2; CD33/CD52, n=1), three sAg (CD22/CD33/CD52, n=13; CD20/CD22/CD52, n=6; CD22/CD52/HER2, n=3; CD22/CD33/HER2, n=1), four sAg (CD20/CD22/CD33/CD52, n=3; CD20/CD22/CD52/HER2, n=1; CD22/CD33/CD52/HER2, n=1). Altogether, 86, 52, 29.5 and 20.5% of the patients were positive for CD22/CD52, CD22/CD33, CD22/CD20 and CD22/HER2, respectively. All CD20 and HER2-positive patients were also positive for CD22 and CD52. Out of the total number of patients 48% were positive for both CD33 and CD52. Interestingly, all Philadelphia-positive B-ALL were positive for CD22 and CD52.

If considering positivity in >90% of the blast population, CD20, CD22, CD33, CD52 and HER2 expression proved to be positive in 16, 95.5, 45.5, 86 and 7% of the patients, respectively. Only one patient was negative for all the tested sAg. Finally, two patients who were analysed at diagnosis, could be also analysed at the time of relapse, and showed no change of sAg expression (unchanged expression of CD22/CD33/CD52 and CD20/CD22/CD33/CD52/HER2).

This series shows that targeted immunotherapy could be considered in almost all patients with B-ALL. The latter might be particularly useful with respect to the use of the commercially available anti-CD22 and anti-CD52 antibodies (>80% of positive patients). Results of monotherapy with single anti-CD20, anti-CD22, anti-CD33 or anti-CD52 therapeutic antibodies have already been reported in a few cases of ALL with some relative efficacy.2, 3, 4, 5 Moreover, we are currently testing the tolerance and efficacy of trastuzumab (Herceptin) in relapsed/refractory B-ALL patients as we have shown that one third of these cases express the HER2 surface antigen.6 In terms of perspective, the next step would be to use the above antibodies as frontline therapy, in combination with standard chemotherapy. As a consequence, some concern could be raised about re-administration of such antibodies at the time of relapse because of the possible risk of the downregulation of their expression at the surface of the leukaemic cells. Indeed, loss of CD20 expression after rituximab is now a well-known phenomenon and interpreted as a mechanism of drug resistance in patients with CD20+ lymphoma.2 However, other studies using the anti-CD33, anti-CD52 or anti-CD22 therapeutic antibodies did not show that downregulation of these sAg is likely to be a common leukaemia-resistance pathway,3, 7, 8 suggesting that they can be used both at the time of diagnosis and relapse in B-ALL.

Our series also suggest that a combination of therapeutic antibodies (with or without chemotherapy) could be envisioned in a majority of patients, at least from a theoretical point of view. The latter proved to be feasible in chronic lymphocytic leukaemia, where the combination of rituximab and Campath has shown efficacy without excessive toxicity.7 Thus, from our results, therapeutic associations combining anti-CD22/anti-CD52, anti-CD22/anti-CD33 or anti-CD33/anti-CD52 may represent attractive candidates for prospective testing in phase 1–2 trials including refractory B-ALL patients.

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Chevallier, P., Robillard, N., Houille, G. et al. Simultaneous study of five candidate target antigens (CD20, CD22, CD33, CD52, HER2) for antibody-based immunotherapy in B-ALL: a monocentric study of 44 cases. Leukemia 23, 806–807 (2009). https://doi.org/10.1038/leu.2008.303

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