Background Story of the widely used ADC Payloads – MMAE&MMAF
To date, there are 15 ADCs that have been approved by the FDA, 6 of which carry MMAE or MMAF as their payload. MMAE and MMAF are the analogs of dolastatin 10, which is famous for its extraordinary cytotoxicity. More than 100 ADC drugs carry a variety of dolastatin 10 analogs and are undergoing preclinical and clinical developments.[1] So let’s take a brief look at the story behind the most widely used ADC payloads - MMAE/MMAF.
Introduction
Dolastatin 10 (later abbreviated as D10, Fig.1) is one of the most potent and broad-spectrum anti-tubulin anticancer agents which was isolated by Pettit et al. from a sea hare Dolabella Auricularia in 1987. [2] The FDA first approved Adcetris as an ADC drug, which is a derivative of D10. Due to the initial clinical failures of D10, subsequent studies focused exclusively on D10 analogs instead of systemic drugs for ADCs.
Fig.1 The isolation, activity and structure of Dolastatin 10
Structural Activity Relationship of D10
Structurally, D10 is a highly potent linear pentapeptide (Fig. 2). In general, the P1−P4 peptide
backbone functional groups and the configuration of D10 are optimal for cellular potency. P5 is the most tolerant position for substitutions, accommodating a variety of small and large groups including aromatic and aliphatic amino acids, excluding highly basic substituents.[4] This modification in P5 allowed for the modulation of physical properties, potencies, and cell permeability or efflux. [5]
Fig.2 Pentapeptide structure of Dolastatin 10
The origin of MMAE/MMAF
At first, scientists put more attention on P5 modification, but significant adverse events were recorded in clinical trials at dose levels that were not sufficient to attain clinical efficacy. An important discovery, the removal of one N-methyl group of P1 at the N-terminus of D10, led to a generation of highly potent and efficacious ADCs. (Fig. 3)[6] Then came MMAE and MMAF! “Then came MMAE and MMAF!”
Fig.3 Key synthetic analogs of D10 which was modified in P1 and P5 respectively.
IC50: half maximal inhibitory concentration; CLogP: a measure of how hydrophilic or hydrophobic a ligand is.
Choice of MMAE and MMAF in the ADC field
MMAE is comparatively more membrane permeable and is more potent (lower cellular IC50) than MMAF. However, MMAF, which is more hydrophilic due to its charged carboxylic terminus, has limited passive diffusion and does not efficiently diffuse out of the cell.
For high tumor expression of target antigens, MMAF is more effective.[7]
For tumors with sparse and heterogeneous expression of the target antigen, MMAE ADCs are advantageous, as the released free drug is subject to efflux by multidrug resistance pumps and can diffuse out of the target cell causing bystander killings.[8]
ChemExpress Advantages
√ All compounds mentioned above in stock
√ Regular storage ofGMP/non-GMPMMAE&MMAF in multiple kilograms
√ 4 US DMF filings related to MMAE (1 MMAE & 2 intermediates; 1 VcMMAE & 1 intermediate)
√ Quality: ≥99% purity, ≥98% ee, ≥99% de, each impurity <0.1%
Reference
[1] Beacon Data Base.
[2] J. Am. Chem. Soc.1987, 109, 6883.
[3] Image from Wikipedia
[4] Anti-Cancer Drug Des.1995, 10, 529.
[5] J. Nat. Prod. 2022,85, 666.
[6] Chem. Pharm. Bull. 1995, 43, 1706.
[7] Br. J. Cancer 2017, 117, 1736.
[8] J. Clin. Invest. 2018,128, 2927.