Table 1.

Examples of T-cell epitope optimization.

Species	Disease	Model Ag	Epitope	MHC	Modification	Functional improvement	Reference
Human	EBV	EBNA 3A	FLRGRAYGL	B*0801	MAL-directed substitution	100 fold increase in sensitivity	Burrows et al. (1992)
Human	CMV	pp65	NLVPMVATV	A*0201	CPL-directed substitution	1,000 to 10,000-fold increase in sensitivity	La Rosa et al. (2001)
Mouse	N/A	Ovalbumin	SIINFEKL	H-2Kb	β-amino acid insertion	500% more stable during serum digestion	Webb et al. (2005)
Mouse	LCMV	glycoprotein	KAVYNFATM	H-2Db	Psi bond insertion	20-fold more stable during protease digestion	Stemmer et al. (1999)
Mouse	keratitis	IgG2a	YFMYSKLRVQKSC	I-Ad	D-amino acid retro-inverso	As active in vivo as the proteogenic peptide	Mézière et al. (1997)
Human	cancer	MAGE/CEA	various	A*0201	MAL-directed substitution	Up to 10,000-fold increase in sensitivity	Tangri et al. (2001)
Human	cancer	gp100	various	A*0201	MHC-anchor substitution	More numbers of T-cells recovered after in vitro prime	Parkhurst et al. (1996)
Human	cancer	PSA	VISNDVCAQV	A*0201	MAL-directed substitution	Better able to induce T-cell activation	Terasawa et al. (2002)
Human	cancer	CEA	YLSGANLNL	A*0201	MAL-directed substitution	1,000-fold increase in sensitivity	Zaremba et al. (1997)
Human	HIV	Gag	TLNAWVKVV	A*0201	CPL-directed substitution	130% increase of T-cells recovered after in vitro prime	Blondelle et al. (2008)
Human	cancer	survivin	ELMLGEFLKL	A*0201	MHC-anchor substitution	Induces stronger T-cell responses in 30% of donors	Bernatchez et al. (2011)
Human	cancer	Melan A	AAGIGILTV	A*0201	CPL-directed substitution	500% increase in TCR/pMHC-binding affinity	Ekeruche-Makinde et al. (2012)
Human	diabetes	preproinsulin	ALWGPDPAAA	A*0201	CPL-directed substitution	100 to 1,000-fold increase in sensitivity	Ekeruche-Makinde et al. (2013)

MAL, monosubstituted analog library; CPL, combinatorial peptide library.