Rationale for use of antibody-drug conjugate to target CD33

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Crosslinking of CD33 on AML cells in vitro can inhibit the proliferation of these cells and activate a process leading to apoptotic cell death (68, 69). First attempts to exploit CD33 for targeted AML therapy in the clinic were undertaken with an unconjugated murine anti-CD33 antibody (M195). Although saturation of CD33 binding sites was observed with doses around 5 mg/m², however, only some patients had transient decreases in peripheral blast counts at this or higher doses (50). Subsequent studies employed a humanized IgG₁ construct of M195, lintuzumab (HuM195; SGN-33), which had >8-fold higher binding avidity than the parent antibody and, unlike M195, demonstrated antibody-dependent cell-mediated cytotoxicity (51, 70). Limited studies pointed towards some activity in APL when used in combination with all-trans retinoic acid (ATRA) in patients in morphological complete remission (CR) (71). On the other hand, lintuzumab had very modest activity as a single agent in overt non-APL AML, with infrequent achievement of CR or partial remission (PR) only amongst patients with relatively low tumor burden even at supra-saturating antibody doses (12-36 mg/m² per day for 4 days x 2 courses) that fully blocked CD33 binding sites throughout a 4-week period (72, 73). Higher doses of lintuzumab (1.5-8 mg/kg/week for 5 weeks, followed by every other week treatment for those who experienced clinical benefit) appeared somewhat more efficacious when investigated in patients with CD33⁺ myeloid malignancies: among the 17 patients with AML, 7 had an objective response (4 morphologic CRs, 2 partial remissions (PRs), and 1 morphologic leukemia-free state) with a median duration of therapy of 25.1 (range, 4.1-57.1) weeks (74).

Two randomized trials have tested lintuzumab together with conventional chemotherapy. In the first, 191 patients with relapsed/refractory AML were randomly assigned to receive mitoxantrone, etoposide, and cytarabine with or without lintuzumab (12 mg/m²). Addition of lintuzumab was associated with an insignificantly higher overall response rate (ORR; CR + CR with incomplete platelet recovery [CRp]: 36% vs. 28%, p=0.28) but unchanged overall survival (OS) (75). In the second, 211 patients older than age 60 with untreated AML were randomized to receive low-dose cytarabine (20 mg subcutaneously twice daily for 10 days) with either lintuzumab (600 mg/week for 4 doses in cycle 1 and every other week for 2 doses in subsequent cycles) or placebo in a double-blinded phase 2b study. Again, addition of lintuzumab did not improve OS (76). Ultimately, because of these negative results, the clinical development of lintuzumab was terminated in 2010.

The lack of significant tumor reducing effects of saturating or supra-saturating doses of unconjugated anti-CD33 antibodies in patients with overt non-APL AML indicated that anti-CD33 antibodies would be useful for AML therapy only if they served as a carrier of another biologically active agent. The feasibility of such an approach was suggested by studies with radiolabeled anti-CD33 antibodies showing selective uptake of the radio-immunoconjugate by AML cells and rapid saturation of leukemic blast cells in peripheral blood and bone marrow at intravenous doses of ≥5mg/m² (50, 52, 77). While the endocytic property of CD33 proved to be a hurdle for the delivery of radioiodine due radio-immunoconjugate internalization and metabolization and, consequently, relatively short residence times in the marrow (50, 52, 77), it spurred efforts to develop CD33-targeting antibody-drug conjugates carrying a toxic payload