IMMU-140, a novel SN-38-antibody-drug conjugate targeting HLA-DR, mediates dual cytotoxic effects in hematological cancers and malignant melanoma

HLA-DR is a member of the MHC class II antigen family expressed on hematological and solid tumors.  Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development.  IMMU-140 is an anti-HLA-DR antibody-drug conjugate comprised of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG₄ antibody (IMMU-114); the IgG₄ naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors.  In vitro, IMMU-140 had dual-therapeutic mechanisms, as evidenced by its retention of non-overlapping anti-HLA-DR non-classical apoptotic signaling and classical apoptosis mediated by its SN-38 payload.   In seven human disease models (acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], multiple myeloma [MM], acute myeloid leukemia [AML], diffuse large B-cell lymphoma [DLBCL], Hodgkin lymphoma [HL], and melanoma), IMMU-140 provided significant therapeutic efficacy compared to controls, in vivo and in 3D spheroid models.  Except for MM and HL, IMMU-140 imparted significantly improved antitumor effects compared to parental IMMU-114.  Even in intractable AML and ALL, where IMMU-114 only had modest antitumor effects,   IMMU-140 therapy mediated >80% improvement in survival.  Therapy was well-tolerated, as demonstrated by no marked loss in body weight.  Combined with doxorubicin, IMMU-140 produced significantly greater antitumor effects in HL than with monotherapy and without any added toxicity.   The dual-therapeutic action of IMMU-140 resulted in promising therapeutic activity in a range of hematopoietic tumors and melanoma, and therefore warrants clinical development.

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