What is Monomethyl Auristatin F (MMAF)?

What is Monomethyl Auristatin F (MMAF)?

Monomethyl auristatin F (MMAF) is a synthetic anti-tumor drug that has been used as a cytotoxic payload molecule in at least six ADCs, and these ADCs have entered clinical trials.

Structure of MMAF

MMAF is a new auristatin derivative with a similar structure to MMAE. The difference between MMAF and MMAE is that the C-terminal of MMAF has a phenylalanine moiety, which can reduce its cytotoxicity and enhance its membrane impermeability. The N-terminal amino group of MMAF has only one methyl substituent.

Structure of MMAF.Figure 1: Structure of MMAF.

Biological Activity of MMAF

Monomethylastatin F (MMAF) is an anti-mitotic agent that inhibits cell division by preventing the polymerization of tubulin. Due to its extremely high toxicity, it cannot be used as a medicine by itself. It is linked to monoclonal antibodies (mAbs) that direct it to cancer cells. The monoclonal antibody linker is stable in the extracellular fluid, but once the conjugate enters the tumor cell, cathepsin will cleave the conjugate, thereby activating the anti-mitotic mechanism.

Structure of a MMAF-mAb-conjugate (from Wikipedia). Figure 2: Structure of a MMAF-mAb-conjugate (from Wikipedia).

ADCs drugs with MMAF

ADCTargetClinical indicationLinkerDevelopment statusDeveloper
AGS-16C3FAGS-16/ENPP3Renal cell carcinoma; liver carcinoma; prostate cancerNon-cleavable maleimidocaproyl (mc) linkerPhase IAgensys/Astellas
AGS-16M8FAGS-16/ENPP3Renal cell carcinoma; liver carcinoma; prostate cancerNon-cleavable maleimidocaproyl (mc) linkerPhase IAgensys/Astellas
ARX788 HER2 ADCHER2Solid Tumors (HER2 over-expressing tumors including breast, gastric, colon, pancreatic and ovarian cancers)A non-natural amino acid linker para-acetyl-phenylalanine (pAcF)Preclinical studies | Phase IZhejiang Medicine Co. | Ambrx
Belantamab mafodotinTNFRSF17Multiple myeloma (BTD and PRIME)Non-cleavable maleimidocaproyl (mc) linkerPhase I Phase II Phase IIIGlaxoSmithKline (GSK)
Co-developer: Seattle Genetics
Denintuzumab mafodotin | SGN-CD19ACD19Oncolog /HematologyNon-cleavable maleimidocaproyl (mc) linker on An average of 4 cysteinylPhase I and Phase IISeattle Genetics
Depatuxizumab Mafodotin | ABT-414EGFR/EGFRde2-7 (EGFRvIII)1L and 2L glioblastoma multiforme (GBM) and solid tumors; squamous cell tumors; non-small-cell lung cancer; pediatric brain tumorsNon-cleavable maleimidocaproyl (mc) linker on an average of 4 cysteinylPhase I and II AbbVie suspends the Phase III UNITE trial in Gliosarcoma and Glioblastoma (NCT03419403 | EudraCT2017-003171-64)AbbVie (prior sponsor, Abbott)
IGN786SAILfollicular lymphoma, diffuse large B-cell lymphoma (DLBCL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); multiple myeloma; pancreatic cancer.Non-cleavable maleimidocaproyl (mc) linkerPreclinicalIgenica Biotherapeutics
LCB14-0110HER2Breast cancer; stomach cancerLegoChem's proprietary linkerPreclinicalLegochem Biosciences and Fosun Pharma
MEDI-547EphA2Solid TumorsNon-cleavable maleimidocaproyl (mc) linkerPhase I; This program was discontinued/terminated for solid tumors (2010)MedImmune
PF 06263507)5T4Solid tumorNon-cleavable maleimidocaproyl (mc) linkerPhase I Status: This program has been discontinued (2015)Oxford BioMedica; Pfizer (Wyeth)
STI-6129CD38Advanced relapsed and/or refractory systemic amyloid light chain (AL) amyloidosisA non-polyethylene glycol linkerPhase ISorrento Therapeutics
Vorsetuzumab mafodotin (SGN-75)CD70Non-Hodgkin’s lymphoma (NHL); renal cell carcinoma (RCC); CD70-positive hematologic malignanciesNon-cleavable maleimidocaproyl (mc) linker An average of 3-5 cysteinylPhase I / Ib This program has been discontinuedSeattle genetics
XMT-1522 | TAK-522HER2  Phase I, discontinued (United States)Mersana Therapeutics, Takeda
ZV05-ADC (5T4-MMAF ADC)5T4 also known as TPBGNSCLC; RCC; colorectal cancer; ovarian cancer; pancreatic cancer; gastric cancers.Proprietary linker Zova Biotherapeutics (Zova Bio); Concortis Biotherapeutics

References:

  1. Tai, Y. T.; Mayes, P. A.; Acharya, C; et al. Novel afucosylated anti-B cell maturation antigen-monomethyl auristatin F antibody-drug conjugate (GSK2857916) induces potent and selective anti-multiple myeloma activity. Blood. 2014;123(20):3128-38.
  2. Dosio, F.; Brusa, P.; Cattel, L. Immunotoxins and Anticancer Drug Conjugate Assemblies: The Role of the Linkage between Components. Toxins. 2011; 3 (12):848-883.
  3. Doronina SO, Mendelsohn BA, Bovee TD, et al. Enhanced activity of monomethyl auristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem. 2006;17(1):114-24.
* Only for research. Not suitable for any diagnostic or therapeutic use.
Inquiry Basket