"2.3. IMGN632: A CD123-Targeting Antibody Drug-Conjugate Recently, the development of a CD123-targeting antibody-drug conjugate (ADC) was reported, which is composed by a humanized anti-CD123 antibody G4723A linked to a DNA mono-alkylating payload of the indolinobenzodiazepine pseudodimer (IGN) class of cytotoxic compounds (called IMGN632) . The activity of IMGN632 was compared to that of X-ADC, the ADC involving the G4723A antibody linked to a DNA crosslinking IGN payload . Both IMG632 and X-ADC exerted both in vitro and in vivo a potent antileukemic eﬀect, but IMGN632 was >40 fold less cytotoxic to the normal myeloid progenitors than X-ADC . Importantly, IMGN632 exerted anti-leukemic eﬀects
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at doses well below those causing cytotoxic eﬀects to myeloid progenitors . Finally, IMGN632 exerted a potent anti-leukemic eﬀect in various AML xenograft models . These observations strongly support the clinical development of IMGN632 . Another recent preclinical study provided evidence that IMGN632 was active in promoting the killing of B-ALL blasts . Thus, Angelova and coworkers provided evidence that CD123 expression was more prevalent in B-ALL than in T-ALL; furthermore, within B-ALLs, CD123 expression was more pronounced in Philadelphia chromosome-positive patients . IMGN362 resulted to be highly cytotoxic to B-ALL, with a half-maximal inhibitory concentration corresponding to the range 0.6–20 pM . These observations support a possible clinical use of IMGN632 for B-ALL targeting. Inlinewiththisstudy,itwasrecentlyreportedthatIMGN632exertedin vivoapronouncedeﬃcacy against patient-derived xenografts (PDXs) derived from a wide range of ALL subtypes, expressing various levels of CD123 . A recent preclinical study explored the targeting of CD123 in BPDCN using IMGN632, showing signiﬁcant anti-leukemic eﬀects, even at a dose of IMGN362 10-fold lower than the anticipated therapeutically active dose . Another recent preclinical study showed a synergism between poly (ADP-ribose) polymerase (PARP) inhibition (using olaparib or other PARP inhibitors under development) to enhance the therapeutic eﬃcacy of IMGN362 across diﬀerent primarily refractory/relapsed AML samples . IMGN362 is currently in phase I evaluation for relapsed/refractory CD123-positive hematological malignancies (NCT 03386513). Recently, the initial safety and antileukemia activity ﬁndings from the dose-escalation stage of this trial were reported, based on the analysis of 12 patients (ﬁve with relapsed/refractory disease and six at ﬁrst relapse; seven patients had adverse cytogenetics and 50% hadsecondaryAML). Theadministrationofthedrugwastolerated,andnomajoradverseevents wereobserved . Of thetreated patients 33% achieveda complete response andthese data support the continuation of this study and further clinical exploration of IMGN362 . Interestingly, a recent study explored a possible anti-leukemic synergism of IMGN362 with the BCL-2 inhibitor venetoclax showing that the combination of the two drugs increases the killing of primary AML blasts; in vitro studies on various AML cell lines indicate additive/synergistic eﬀects of the two drugs and in vivo the combination of the two drugs clearly prolongs survival and increases anti-leukemic activity in various AML PDX models . These observations strongly support the clinical exploration of the combination of these two drugs in a clinical trial in AML patients."