Indatuximab ravtansine is a monoclonal antibody-linked cytotoxic agent that specifically targets CD138-expressing cells. Monotherapy has been shown to significantly inhibit multiple myeloma tumour growth in vivo and improve host survival. Here, we show that in most cell lines tested, indatuximab ravtansine acts additively or even synergistically with clinically approved therapies for treatment of multiple myeloma. In addition, in vivo mouse xenograft models confirmed the activity of indatuximab ravtansine in combination with lenalidamide and lenalidomide/dexamethasone. Indatuximab ravtansine may therefore be a suitable combination partner for multiple myeloma, and a clinical study is ongoing.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0380-0) contains supplementary material, which is available to authorized users.
PurposeTriple-negative breast cancer (TNBC) is related with a poor prognosis as patients do hardly benefit from approved therapies. CD138 (Syndecan-1) is upregulated on human breast cancers. Indatuximab ravtansine (BT062) is an antibody-drug-conjugate that specifically targets CD138-expressing cells and has previously shown clinical activity in multiple myeloma. Here we show indatuximab ravtansine as a potential mono- and combination therapy for TNBC.MethodsThe effects of indatuximab ravtansine were assessed in vitro in SK-BR-3 and T47D breast cancer cell lines. The in vivo effects of indatuximab ravtansine alone and in combination with docetaxel or paclitaxel were assessed in MAXF401, MAXF1384 and MAXF1322 xenograft TNBC models.ResultsCD138+ SK-BR-3 and T47D cells were highly sensitive to indatuximab ravtansine. The high CD138-expressing MAXF401 xenograft model demonstrated strong inhibition of tumor growth with 4 mg/kg indatuximab ravtansine. High doses of indatuximab ravtansine (8 mg/kg), docetaxel and the combination of both led to complete remission. In the low CD138-expressing MAXF1384 xenograft model, only combination of indatuximab ravtansine and docetaxel demonstrated a significant efficacy. In the MAXF1322 xenograft model, indatuximab ravtansine alone and in combination with paclitaxel elicited complete remission.ConclusionsThese data demonstrate potential use of indatuximab ravtansine in combination with docetaxel or paclitaxel for CD138-positive TNBC.
3008 Background: BT062 represents a CD138 specific antibody-drug conjugate comprising a chimerized anti-CD138 antibody conjugated to maytansinoid (DM4), an inhibitor of tubulin polymerization. CD138 (syndecan-1) which is highly upregulated on neoplastic plasma cells, is currently used as a standard identification marker for multiple myeloma (MM) and provides therefore a promising target for therapeutic intervention in MM. We have previously reported that BT062 exerts high selective in vitro and in vivo cytotoxic activity against CD138 positive MM cells (Ikeda et al., Clin Cancer Res. 2009; 15(12)). Based on these results, a Phase I clinical trial has been conducted in relapsed/refractory MM patients, which demonstrated an acceptable toxicity profile after repeated administration of single doses up to 160 mg/m2, as well as first signs of clinical activity in heavily pretreated patients (Chanan-Khan et al., ASH 2009). Here, we investigated the anti-myeloma efficacy of BT062 when combined with clinically approved myeloma drugs in vitro and in experimental animals in vivo. Methods and Results: In vitro drug combination studies on different myeloma cell lines indicated that BT062 exerts synergistic cytotoxic activity when combined for example with lenalidomide on RPMI8226 myeloma cells. None of the myeloma drug combinations with BT062 resulted in a strong antagonistic effect. Lenalidomide and bortezomib, representing novel established anti-myeloma drugs, were further tested for combination with BT062 in SCID mice bearing MOLP-8 MM xenografts. A single intravenous injection of BT062 was active against these tumors (400 μg/kg: T/C = 7%, Log cell kill (LCK) = 2.7) without signs of toxicity (no body weight loss). Monotherapy of bortezomib (1 mg/kg, twice weekly for 2 weeks) was inactive against the MOLP-8 xenografts. However, when combined with BT062, a superior anti-tumor effect compared to BT062 monotherapy was observed: Single injection of BT062 at different concentrations (100 μg/kg, 200 μg/kg, 400 μg/kg) followed by i.v. administration of bortezomib (1 mg/kg, twice weekly for 2 weeks) resulted in a dose dependent inhibition of tumor cell growth (at 200 μg/kg: LCK = 2.0; T/C = 7%, at 400 μg/kg LCK = 3.2; T/C = 7%). No increased in toxicity have been observed in the combination treatment compared to each monotherapy. BT062 was further evaluated for combination with lenalidomide which was administered intraperitoneally, daily for 5 days (2 weeks in total): BT062 administered alone at concentrations of 400 μg/kg was highly active against the MOLP-8 tumors reflected by a LCK of 2.5 (T/C = 13%). A lower anti-tumor effect has been observed by lenalidomide monotherapy (LCK = 0.8, T/C = 38%). Combination of both drugs demonstrated superior anti-tumor activity compared to each monotherapy (e.g. 400 μg/kg BT062 + lenalidomide: LCK = 3.5; T/C = 8%). Remarkably, neither body weight loss nor symptoms of illness have been observed confirming that this combination is also well tolerated. Conclusion: These data demonstrate that BT062 is not only effective in MM monotherapy but represents further a promising candidate for combination with currently used anti-MM drugs such as bortezomib or lenalidomide. No increased toxicities have been observed in all in vivo xenograft studies indicating that BT062 combined with other cytotoxic compounds might be well tolerated in MM therapy. Interestingly, although BT062 has been administered as a single dose, the anti-tumor effect in combination with either bortezomib or lenalidomide was significantly enhanced. These data provide a rationale to further investigate BT062 in clinical combination trials. Disclosures: Zuber: Biotest AG: Employment. Daelken:Biotest AG: Employment. Aigner:Biotest AG: Employment. Haeder:Biotest AG: Employment. Ab:ImmunoGen, Inc.: Employment. Whiteman:ImmunoGen, Inc.: Employment. Lutz:ImmunoGen, Inc.: Employment. Osterroth:Biotest AG: Employment. Uherek:Biotest AG: Employment.
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