Investigational CD33-targeted therapeutics for acute myeloid leukemia

ABSTRACT

Introduction: There is long-standing interest in drugs targeting the myeloid differentiation antigen CD33 in acute myeloid leukemia (AML). Positive results from randomized trials with the antibody-drug conjugate (ADC) gemtuzumab ozogamicin (GO) validate this approach. Partly stimulated by the success of GO, several CD33-targeted therapeutics are currently in early phase testing.

Areas covered: CD33-targeted therapeutics in clinical development include Fc-engineered unconjugated antibodies (BI 836858 [mAb 33.1]), ADCs (SGN-CD33A [vadastuximab talirine], IMGN779), radioimmunoconjugates (²²⁵Ac-lintuzumab), bi- and trispecific antibodies (AMG 330, AMG 673, AMV564, 161533 TriKE fusion protein), and chimeric antigen receptor (CAR)-modified immune effector cells. Besides limited data on ²²⁵Ac-lintuzumab showing modest single-agent activity, clinical data are so far primarily available for SGN-CD33A. SGN-CD33A has single-agent activity and has shown encouraging results when combined with an azanucleoside or standard chemotherapeutics. However, concerns about toxicity to the liver and normal hematopoietic cells – the latter leading to early termination of a phase 3 trial – have derailed the development of SGN-CD33A, and its future is uncertain.

Expert opinion: Early results from a new generation of CD33-targeted therapeutics are anticipated in the next 2–3 years. Undoubtedly, re-approval of GO in 2017 has changed the landscape and rendered clinical development for these agents more challenging.

KEYWORDS:

• Acute myeloid leukemia (AML)
• adoptive immunotherapy
• antibody
• antibody–drug conjugate
• bispecific antibody
• CD33
• chimeric antigen receptor
• immunotoxin
• radioimmunotherapy
• trispecific antibody

Article highlights

• Positive results with the antibody–drug conjugate (ADC) gemtuzumab ozogamicin (GO) validate CD33 as target for AML immunotherapy.

• A new generation of CD33-targeted therapeutics spanning the spectrum of unconjugated and conjugated monoclonal antibodies, bi- and trispecific antibodies, and chimeric antigen receptor (CAR)-modified immune effector cells is currently in early phase testing.

• Except for ²²⁵Ac-lintuzumab and SGN-CD33A, clinical data on these therapeutics have not yet been reported.

• ²²⁵Ac-lintuzumab has modest single-agent activity.

• SGN-CD33A has single-agent activity, and ‘encouraging’ results have been observed combined with DNA methyltransferase inhibitors and standard chemotherapeutics, but concerns over risk of SOS/VOD and toxicity to normal hematopoietic cells render its future uncertain.

• The experience with SGN-CD33A highlights the importance of patient selection for the testing/use of potent CD33-directed drugs.

• Re-approval of GO in 2017 has raised the bar for new CD33-targeted therapeutics and made their development more challenging.

This box summarizes key points contained in the article.

Declaration of interest

R. Walter has received laboratory research grants and/or clinical trial support from Actinium Pharmaceuticals, Inc., Amgen Inc., Amphivena Therapeutics, Inc., Aptevo Therapeutics, Inc., Covagen AG, and Seattle Genetics, Inc.; has ownership interests with Amphivena Therapeutics, Inc.; and is (or has been) a consultant to Amphivena Therapeutics, Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, Covagen AG, Emergent Biosolutions, Inc. (now Aptevo Therapeutics, Inc.), Pfizer, Inc., and Seattle Genetics, Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.