A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells

Abstract

The outlook for patients with refractory/relapsed acute myeloid leukemia (AML) remains poor, with conventional chemotherapeutic treatments often associated with unacceptable toxicities, including severe infections due to profound myelosuppression. Thus there exists an urgent need for more effective agents to treat AML that confer high therapeutic indices and favorable tolerability profiles. Because of its high expression on leukemic blast and stem cells compared with normal hematopoietic stem cells and progenitors, CD123 has emerged as a rational candidate for molecularly targeted therapeutic approaches in this disease. Here we describe the development and preclinical characterization of a CD123-targeting antibody-drug conjugate (ADC), IMGN632, that comprises a novel humanized anti-CD123 antibody G4723A linked to a recently reported DNA mono-alkylating payload of the indolinobenzodiazepine pseudodimer (IGN) class of cytotoxic compounds. The activity of IMGN632 was compared with X-ADC, the ADC utilizing the G4723A antibody linked to a DNA crosslinking IGN payload. With low picomolar potency, both ADCs reduced viability in AML cell lines and patient-derived samples in culture, irrespective of their multidrug resistance or disease status. However, X-ADC exposure was >40-fold more cytotoxic to the normal myeloid progenitors than IMGN632. Of particular note, IMGN632 demonstrated potent activity in all AML samples at concentrations well below levels that impacted normal bone marrow progenitors, suggesting the potential for efficacy in AML patients in the absence of or with limited myelosuppression. Furthermore, IMGN632 demonstrated robust antitumor efficacy in multiple AML xenograft models. Overall, these findings identify IMGN632 as a promising candidate for evaluation as a novel therapy in AML.

Passive Monoclonal and Polyclonal Antibody Therapies

“…Novel therapies have been developed in the last decade, some showing temporal success and some showing a brighter tomorrow. 216 AMG330 is a bispecific T-cell engager (BiTE) antibody with specificity for CD3 and CD33. This Mab is currently in clinical trials to be completed in 2020 for treatment of AML.…”

“…Ongoing clinical trials will be completed in 2021. 216 Talacotuzumab is a humanized monoclonal antibody (IgG1-2k) with specificity to interleukin (IL)-3 receptor subunit-a (CD123, a growth and differentiating receptor). This antibody induces ADCC both in vitro and in animal models.…”

New and Emerging Targeted Therapies for Pediatric Acute Myeloid Leukemia (AML)

“…CD123, the alpha subunit of the IL-3 receptor, is overexpressed in multiple hematologic malignancies, including AML, ALL, and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Because of its high expression on leukemic blasts as compared with normal hematopoietic stem cells, CD123 has emerged as an attractive candidate for molecularly targeted therapeutics [25]. Tagraxofusp-erzs (Elzonris, Stemline) and IMGN632 (immunogen) are two anti-CD123-directed immunotoxins which have been developed in recent years.…”

“…IMGN632 is comprised of a novel humanized anti-CD123 antibody, G4723A, linked to a unique DNA-alkylating payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class of cytotoxic compounds [25,29]. Kovtun et al showed that IMGN632 demonstrated potent activity in all AML samples at concentrations well below levels that impacted normal bone marrow progenitors and exhibited robust antitumor activity with a wide therapeutic index in multiple AML xenografts [25].…”

DNA damaging agent-based antibody-drug conjugates for cancer therapy

“…It resulted in 600 times more potency in vitro , which makes the PBD dimer an attractive payload for ADCs. There are 13 ADCs [Vadastuximab talirine/SGN-CD33A [27–29],SGN-CD70A [30], SGN-CD19B, SGN-CD123A [31], SGN-CD352A [32], Rovalpituzumab tesirine/Rova-T [33–35], ADCT-301/HuMax-TAC-PBD [36], ADCT-402 [37], MEDI3726/ADC-401, IMGN779 [38], IMGN632 [39], SC-002 and SC-003] with PBD payloads currently being tested in clinical trials. There are two possible reasons that make PBDs the most prominent class of DNA-damaging payloads: (1) PBDs have picomolar activity in vitro and demonstrated therapeutic index in clinic [40].…”