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plays a key inhibitory role on T cells. We also found that HL cell line supernatant inhibited normal B-cell prolifera- tion (data not shown). Other cytokines or soluble factors from the KM-H2 supernatant may also contribute to the inhibitory effect, e.g., sCD30. An 85kDa soluble form of the CD30 molecule (sCD30) has been shown to be released by CD30+ cells in vitro and in vivo. sCD30 was ele- vated in the serum of HL41,42 and other CD30-expressing tumors, as well as inflammatory conditions with strong T- or B-cell activation. The CD30-Fc fusion protein inhibits T-cell proliferation,43 whilst sCD30 is also involved in the pathogenesis of renal, islet transplant rejection.44,45 The effect of brentuximab on sCD30 has not been investigat- ed. The thymus and activation related chemokine (TARC; CCL17) is expressed by HRS cells.46
TARC is confirmed as a biomarker of HL, since elevated serum TARC reflected the disease activity and correlated with clinical response.47,48 Herein, as well as confirming elevation of serum sCD83 in active HL, we monitored sCD83 on six HL patients who underwent sequential cycles of chemotherapy. A complete response shown by PET-CT scan correlated with the decreased sCD83 levels. Thus sCD83 may be another biomarker candidate for monitoring the potential clinical response. A much larger cohort of HL patients will be monitored prospectively in order to explore this further. Additional investigations regarding the effect of sCD83 on HL biology may well assist therapeutic development in HL. Natural sCD83 has proved difficult to obtain for functional studies, suggesting the sCD83 structure and/or function is sensitive to in vitro manipulation.49
We have developed a human anti-human CD83 mAb, 3C12C, to investigate in clinical trials. It kills HL cells through ADCC, but in order to enhance its activity, we developed a 3C12C toxin conjugate (3C12C-MMAE).
The unconjugated parent anti-CD30 antibody SGN-30 had no effect on HL in a study of 38 patients.50 Brentuximab vedotin SGN35, which is a drug conjugate of SGN-30 with MMAE, has, however, proven to be a highly promising drug with CD30+ lymphoma.10 We found 3C12C-MMAE kills CD83+ HL cell lines KM-H2 and HDLM2 very efficiently. Although HDLM2 cells express less surface CD83 and are resistant to ADCC killing, the high killing efficiency of HDLM2 with 3C12C-MMAE is likely related to the rapid antibody internalization and high intracellular CD83 turnover. 3C12C binding on L428 is relatively stable, rendering it sensitive to killing by ADCC, but less likely to be killed with 3C12C-MMAE, which is mediated via antibody internalization. Further improvements in the 3C12C- MMAE conjugate preparation are planned.
Finally, we tested the safety of 3C12C in non-human primates. We saw no clinical toxicity, abnormalities of blood count, liver or renal function or a decrease in the tar- get CD1c+DC population (data not shown). By monitoring B cells, we saw depletion in the blood and lymph nodes. The depletion of activated CD83+ B cells led to a signifi- cant reduction in the B-cell area of lymph nodes. This early evidence of CD83 target cell depletion in non-human primates is most encouraging, suggesting an ADCC effect that should translate readily to the clinic.
Taken together, these data demonstrate that CD83 is a new potential diagnostic HL marker and serum sCD83 levels are likely to reflect HL disease load. CD83 is a target for therapeutic mAb development as well as CD83 target derivatives. The potential therapeutic human anti-CD83 antibody, 3C12C, kills HL cells efficiently in vitro. It is safe in non-human primates, and depletes CD83+ target cells. Further development of 3C12C in human studies merits serious consideration.
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