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Dose, timing, schedule, and the choice of targeted epitope alter the efficacy of anti-CD22 immunotherapy in mice bearing human lymphoma xenografts.

O'Donnell RT, Ma Y, McKnight HC, Pearson D, Tuscano JM - Cancer Immunol. Immunother. (2009)

Bottom Line: HB22.27 had minimal effect, whereas HB22.7 improved survival and shrank tumors substantially.HB22.7 doses greater than 1.4 mg/week did not further increase efficacy (or toxicity).Various schedules of HB22.7 administration were tested; one dose every other week was more effective than more or less frequent dosing.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, Cancer Center, Suite 3016, Sacramento, CA 95817, USA. robert.odonnell@ucdmc.ucdavis.edu

ABSTRACT
CD22 is a cell-surface adhesion molecule on most B-cell NHL, so it is a promising target for immunotherapy. HB22.7 is an anti-CD22 mAb that binds the two NH(2)-terminal immunoglobulin domains and specifically blocks the interaction of CD22 with its ligand. CD22-blocking mAbs induce apoptosis in neoplastic B-cells and are functionally distinguishable from other anti-CD22 mAbs. This study assessed the optimal dose, route, schedule, and the targeted CD22 epitope. Raji NHL-bearing nude mice were studied. A non-blocking anti-CD22 mAb (HB22.27) was used as a control. HB22.27 had minimal effect, whereas HB22.7 improved survival and shrank tumors substantially. HB22.7 doses greater than 1.4 mg/week did not further increase efficacy (or toxicity). Tumors less than 200 mm(3) had a higher response rate than did larger tumors. Various schedules of HB22.7 administration were tested; one dose every other week was more effective than more or less frequent dosing. Pharmacokinetic studies revealed that the half-life of HB22.7 was 28 days; this correlated with the time needed to re-populate cell-surface CD22 after treatment with HB22.7. Immuno-PET showed that NHL was rapidly and specifically targeted by copper-64-labeled-HB22.7. This study provided data as to an optimal dose, route, schedule and interval between doses of HB22.7.

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The effect of starting tumor volume on the efficacy of HB22.7. Treatment of tumors that were initially large (>200 mm3) was compared with treatment of smaller tumors (<200 mm3). In the treatment group having smaller tumors, there was more tumor shrinkage when compared to tumors that were initially >200 mm3. Control mice n = 20; HB22.7-treated mice >200 mm3, n = 5; HB22.7-treated mice <200 mm3, n = 21
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Fig2: The effect of starting tumor volume on the efficacy of HB22.7. Treatment of tumors that were initially large (>200 mm3) was compared with treatment of smaller tumors (<200 mm3). In the treatment group having smaller tumors, there was more tumor shrinkage when compared to tumors that were initially >200 mm3. Control mice n = 20; HB22.7-treated mice >200 mm3, n = 5; HB22.7-treated mice <200 mm3, n = 21

Mentions: Multiple studies were performed using HB22.7 to treat nude mice bearing Raji xenografts. Similar to what is seen after treatment with rituximab, it was observed that some mice had CRs but some mice did not respond at all. One factor that related to the response and survival was the size of the initial tumor, Fig. 2. HB22.7 was much more effective when the initial size of the tumor was less than 200 mm3. The CR rate, tumor volume reduction, and survival were all better when tumors were less than 200 mm3 at the time of HB22.7 administration. In this experiment, untreated controls had a spontaneous remission rate of 5% (one PR). Mice with tumors less than 200 mm3 when treated with one dose of HB22.7 had a 48% RR (33% CRs and 15% PRs), in addition to flattening of the tumor growth rate. Mice with tumors greater than 200 mm3, when treated with one dose of HB22.7 had no shrinkage that qualified for even a PR (although their growth rate slowed). The difference between response rates for small tumors versus untreated controls was significant (P = 0.012), however, there was no significant difference between the response rate of untreated controls and mice bearing xenografts greater than 200 mm3. Similarly, the difference in CRs between the small treated xenografts and untreated controls was P = 0.015.Fig. 2


Dose, timing, schedule, and the choice of targeted epitope alter the efficacy of anti-CD22 immunotherapy in mice bearing human lymphoma xenografts.

O'Donnell RT, Ma Y, McKnight HC, Pearson D, Tuscano JM - Cancer Immunol. Immunother. (2009)

The effect of starting tumor volume on the efficacy of HB22.7. Treatment of tumors that were initially large (>200 mm3) was compared with treatment of smaller tumors (<200 mm3). In the treatment group having smaller tumors, there was more tumor shrinkage when compared to tumors that were initially >200 mm3. Control mice n = 20; HB22.7-treated mice >200 mm3, n = 5; HB22.7-treated mice <200 mm3, n = 21
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2749165&req=5

Fig2: The effect of starting tumor volume on the efficacy of HB22.7. Treatment of tumors that were initially large (>200 mm3) was compared with treatment of smaller tumors (<200 mm3). In the treatment group having smaller tumors, there was more tumor shrinkage when compared to tumors that were initially >200 mm3. Control mice n = 20; HB22.7-treated mice >200 mm3, n = 5; HB22.7-treated mice <200 mm3, n = 21
Mentions: Multiple studies were performed using HB22.7 to treat nude mice bearing Raji xenografts. Similar to what is seen after treatment with rituximab, it was observed that some mice had CRs but some mice did not respond at all. One factor that related to the response and survival was the size of the initial tumor, Fig. 2. HB22.7 was much more effective when the initial size of the tumor was less than 200 mm3. The CR rate, tumor volume reduction, and survival were all better when tumors were less than 200 mm3 at the time of HB22.7 administration. In this experiment, untreated controls had a spontaneous remission rate of 5% (one PR). Mice with tumors less than 200 mm3 when treated with one dose of HB22.7 had a 48% RR (33% CRs and 15% PRs), in addition to flattening of the tumor growth rate. Mice with tumors greater than 200 mm3, when treated with one dose of HB22.7 had no shrinkage that qualified for even a PR (although their growth rate slowed). The difference between response rates for small tumors versus untreated controls was significant (P = 0.012), however, there was no significant difference between the response rate of untreated controls and mice bearing xenografts greater than 200 mm3. Similarly, the difference in CRs between the small treated xenografts and untreated controls was P = 0.015.Fig. 2

Bottom Line: HB22.27 had minimal effect, whereas HB22.7 improved survival and shrank tumors substantially.HB22.7 doses greater than 1.4 mg/week did not further increase efficacy (or toxicity).Various schedules of HB22.7 administration were tested; one dose every other week was more effective than more or less frequent dosing.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, Cancer Center, Suite 3016, Sacramento, CA 95817, USA. robert.odonnell@ucdmc.ucdavis.edu

ABSTRACT
CD22 is a cell-surface adhesion molecule on most B-cell NHL, so it is a promising target for immunotherapy. HB22.7 is an anti-CD22 mAb that binds the two NH(2)-terminal immunoglobulin domains and specifically blocks the interaction of CD22 with its ligand. CD22-blocking mAbs induce apoptosis in neoplastic B-cells and are functionally distinguishable from other anti-CD22 mAbs. This study assessed the optimal dose, route, schedule, and the targeted CD22 epitope. Raji NHL-bearing nude mice were studied. A non-blocking anti-CD22 mAb (HB22.27) was used as a control. HB22.27 had minimal effect, whereas HB22.7 improved survival and shrank tumors substantially. HB22.7 doses greater than 1.4 mg/week did not further increase efficacy (or toxicity). Tumors less than 200 mm(3) had a higher response rate than did larger tumors. Various schedules of HB22.7 administration were tested; one dose every other week was more effective than more or less frequent dosing. Pharmacokinetic studies revealed that the half-life of HB22.7 was 28 days; this correlated with the time needed to re-populate cell-surface CD22 after treatment with HB22.7. Immuno-PET showed that NHL was rapidly and specifically targeted by copper-64-labeled-HB22.7. This study provided data as to an optimal dose, route, schedule and interval between doses of HB22.7.

Show MeSH
Related in: MedlinePlus