The Enemy Within

Imagine your body's own blood-producing factories—the bone marrow—being taken over by defective cells that multiply uncontrollably, crowding out healthy cells and failing to mature into functional infection-fighting troops. This isn't science fiction; this is the reality for patients diagnosed with acute myeloid leukemia (AML), an aggressive blood cancer that affects approximately 20,000 new patients each year in the United States alone .

For those whose disease returns after initial treatment or proves resistant to conventional therapies, the outlook has historically been grim. But what if we could design a precision-guided weapon that seeks out and destroys these cancerous cells while sparing healthy tissues? This is the promise of IMGN632 (now known as pivekimab sunirine), a novel antibody-drug conjugate that represents a groundbreaking approach in the fight against AML and other CD123-positive hematologic malignancies.

Understanding Acute Myeloid Leukemia and the Need for Better Treatments

The Challenge of Relapsed/Refractory Disease

While initial treatments (including intensive chemotherapy and stem cell transplants) can induce remission in many AML patients, the disease often returns—a condition known as relapsed AML. In some cases, the cancer proves resistant to initial treatment from the start, termed refractory AML. Patients in these categories face significantly limited options, as their cancer cells have often developed defenses against conventional chemotherapy drugs. Until recently, the treatment landscape for these patients has seen limited innovation, creating an urgent need for therapies that work through novel mechanisms to overcome these resistance pathways.

The Science of Precision Targeting: CD123 as an Achilles' Heel

The Making of a Smart Weapon: Antibody-Drug Conjugate Technology

What Are Antibody-Drug Conjugates?

Antibody-drug conjugates (ADCs) represent a revolutionary class of targeted cancer therapies that combine the precision of antibody-based targeting with the potent cell-killing ability of traditional chemotherapy. Think of them as sophisticated drug delivery systems composed of three key elements:

The Innovative Engineering of IMGN632

IMGN632 incorporates several advanced design features that make it particularly promising:

• A high-affinity anti-CD123 antibody that tightly binds to the CD123 target on cancer cells Targeting
• A cleavable peptide linker that remains stable in circulation but efficiently releases the payload inside cancer cells Stability
• A novel indolinobenzodiazepine pseudodimer (IGN) payload that alkylates DNA and causes single-strand breaks, leading to cell death ^{1 7} Potency

This specific payload class was selected because it demonstrates high potency against tumor cells while showing significantly less toxicity to normal marrow progenitors than other DNA-targeting payloads, potentially translating to better safety profiles in patients .

ADC Mechanism of Action

Illustration of antibody-drug conjugate targeting cancer cells

Inside the Groundbreaking Clinical Trial: Design and Approach

Study Structure and Patient Population

The phase I, first-in-human study of IMGN632 was designed as an open-label trial conducted across nine hospitals in France, Italy, Spain, and the United States ¹ . The trial followed a dose-escalation design, where small groups of patients received progressively higher doses of the drug to determine the optimal balance between effectiveness and safety. The study enrolled patients aged 18 years or older with CD123-positive hematologic malignancies who had experienced relapse or become refractory to previous treatments—a population with particularly limited options.

Dosing Strategies Evaluated

The trial systematically evaluated two different dosing approaches:

This careful, step-wise approach allowed researchers to meticulously monitor how the drug was tolerated at each dose level and identify any potential side effects early.

What the Research Revealed: Safety and Efficacy Findings

Establishing the Safety Profile

One of the primary goals of any first-in-human trial is to evaluate the safety of a new investigational drug and determine the appropriate dose for future studies. In this trial, IMGN632 demonstrated a manageable safety profile across the dose ranges tested ¹ .

Importantly, no tumor lysis syndrome, capillary leak syndrome, or cytokine release syndrome were reported—side effects that have been problematic with some other targeted therapies ⁴ .

Evidence of Anti-Leukemia Activity

Beyond establishing safety, the trial provided promising early evidence of IMGN632's ability to fight cancer. At the recommended phase 2 dose of 0.045 mg/kg every 3 weeks, the overall response rate was 21% (6 of 29 patients), with a composite complete remission rate of 17% (5 of 29 patients) ¹ . While these percentages might seem modest at first glance, they represent significant achievement in a population of patients who had exhausted multiple prior treatment options and had progressive disease despite conventional approaches.

The research team also observed that IMGN632 demonstrated activity across multiple CD123-positive hematologic malignancies, not just AML. This broad applicability is particularly promising given the mechanism of action targeting CD123, which is expressed across several difficult-to-treat blood cancers ³ .

Beyond the Lab: Real-World Impact and Future Directions

From Monotherapy to Combination Approaches

Building on the promising phase I results, research with IMGN632 has expanded to explore its potential in combination with other established AML treatments. Preclinical data demonstrated synergy between IMGN632 and both azacitidine and venetoclax—two drugs used in AML treatment—including evidence that the combination could overcome resistance to these agents in laboratory models ⁴ .

This scientific rationale supported the launch of a phase 1b/2 clinical trial evaluating the triplet combination of IMGN632 with azacitidine and venetoclax in patients with CD123-positive AML. Early results have been encouraging, showing a manageable safety profile and promising anti-leukemia activity in this challenging relapsed/refractory population ⁴ . In higher-intensity cohorts of this combination study, response rates were particularly notable, with an objective response rate of 75% and composite complete remission rate of 40% ⁴ .

Special Populations and Additional Applications

The research has also revealed particularly promising activity in specific molecular subtypes of AML. For example, in patients with FLT3 mutations—a subgroup that often has poorer outcomes—the triplet combination demonstrated remarkable activity, with 100% objective response rate and 71% composite complete remission rate in a small subset of patients ⁴ . Additionally, research continues to explore the potential of IMGN632 in blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and aggressive hematologic malignancy with high CD123 expression .