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Msg  50059 of 50129  at  11/14/2019 8:44:04 PM  by

jv08201


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"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) [117]. The activity of IMGN632 was compared to that of X-ADC, the ADC involving the G4723A antibody linked to a DNA crosslinking IGN payload [130]. 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 [130]. Importantly, IMGN632 exerted anti-leukemic effects
Cancers 2019, 11, 1358 15 of 31
at doses well below those causing cytotoxic effects to myeloid progenitors [130]. Finally, IMGN632 exerted a potent anti-leukemic effect in various AML xenograft models [130]. These observations strongly support the clinical development of IMGN632 [130]. Another recent preclinical study provided evidence that IMGN632 was active in promoting the killing of B-ALL blasts [87]. 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 [87]. IMGN362 resulted to be highly cytotoxic to B-ALL, with a half-maximal inhibitory concentration corresponding to the range 0.6–20 pM [87]. 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 [131]. 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 [132]. 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 [133]. 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)[134]. Theadministrationofthedrugwastolerated,andnomajoradverseevents wereobserved [134]. Of thetreated patients 33% achieveda complete response andthese data support the continuation of this study and further clinical exploration of IMGN362 [134]. 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 [135]. These observations strongly support the clinical exploration of the combination of these two drugs in a clinical trial in AML patients."
 https://pdfs.semanticscholar.org/dbc9/19a1fba0689d7f0dddd898a66cdbaaa358cb.pdf?_ga=2.244532929.590749224.1573781563-874621307.1531511725
 
 
 


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