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.
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.
Figure 1: Structure 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.
Figure 2: Structure of a MMAF-mAb-conjugate (from Wikipedia).
|ADC||Target||Clinical indication||Linker||Development status||Developer|
|AGS-16C3F||AGS-16/ENPP3||Renal cell carcinoma; liver carcinoma; prostate cancer||Non-cleavable maleimidocaproyl (mc) linker||Phase I||Agensys/Astellas|
|AGS-16M8F||AGS-16/ENPP3||Renal cell carcinoma; liver carcinoma; prostate cancer||Non-cleavable maleimidocaproyl (mc) linker||Phase I||Agensys/Astellas|
|ARX788 HER2 ADC||HER2||Solid 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 I||Zhejiang Medicine Co. | Ambrx|
|Belantamab mafodotin||TNFRSF17||Multiple myeloma (BTD and PRIME)||Non-cleavable maleimidocaproyl (mc) linker||Phase I Phase II Phase III||GlaxoSmithKline (GSK) |
Co-developer: Seattle Genetics
|Denintuzumab mafodotin | SGN-CD19A||CD19||Oncolog /Hematology||Non-cleavable maleimidocaproyl (mc) linker on An average of 4 cysteinyl||Phase I and Phase II||Seattle Genetics|
|Depatuxizumab Mafodotin | ABT-414||EGFR/EGFRde2-7 (EGFRvIII)||1L and 2L glioblastoma multiforme (GBM) and solid tumors; squamous cell tumors; non-small-cell lung cancer; pediatric brain tumors||Non-cleavable maleimidocaproyl (mc) linker on an average of 4 cysteinyl||Phase I and II AbbVie suspends the Phase III UNITE trial in Gliosarcoma and Glioblastoma (NCT03419403 | EudraCT2017-003171-64)||AbbVie (prior sponsor, Abbott)|
|IGN786||SAIL||follicular lymphoma, diffuse large B-cell lymphoma (DLBCL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); multiple myeloma; pancreatic cancer.||Non-cleavable maleimidocaproyl (mc) linker||Preclinical||Igenica Biotherapeutics|
|LCB14-0110||HER2||Breast cancer; stomach cancer||LegoChem's proprietary linker||Preclinical||Legochem Biosciences and Fosun Pharma|
|MEDI-547||EphA2||Solid Tumors||Non-cleavable maleimidocaproyl (mc) linker||Phase I; This program was discontinued/terminated for solid tumors (2010)||MedImmune|
|PF 06263507)||5T4||Solid tumor||Non-cleavable maleimidocaproyl (mc) linker||Phase I Status: This program has been discontinued (2015)||Oxford BioMedica; Pfizer (Wyeth)|
|STI-6129||CD38||Advanced relapsed and/or refractory systemic amyloid light chain (AL) amyloidosis||A non-polyethylene glycol linker||Phase I||Sorrento Therapeutics|
|Vorsetuzumab mafodotin (SGN-75)||CD70||Non-Hodgkin’s lymphoma (NHL); renal cell carcinoma (RCC); CD70-positive hematologic malignancies||Non-cleavable maleimidocaproyl (mc) linker An average of 3-5 cysteinyl||Phase I / Ib This program has been discontinued||Seattle genetics|
|XMT-1522 | TAK-522||HER2||Phase I, discontinued (United States)||Mersana Therapeutics, Takeda|
|ZV05-ADC (5T4-MMAF ADC)||5T4 also known as TPBG||NSCLC; RCC; colorectal cancer; ovarian cancer; pancreatic cancer; gastric cancers.||Proprietary linker||Zova Biotherapeutics (Zova Bio); Concortis Biotherapeutics|