Development and properties of hypoallergenic infant formula

Woel-Kyu Ha; Jeongmin Lee; Kyu-Earn Kim

doi:10.4168/aard.2017.5.2.63

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Ha, Lee, and Kim: Development and properties of hypoallergenic infant formula

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Allergy, Asthma & Respiratory Disease 2017; 5(2): 63-72.

Published online: 31 March 2017

DOI: https://doi.org/10.4168/aard.2017.5.2.63

Development and properties of hypoallergenic infant formula

Woel-Kyu Ha¹

, Jeongmin Lee¹, Kyu-Earn Kim²

¹Research and Development Center, Maeil Dairies Co., Ltd., Pyeongtaek, Korea.

²Development of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.

Correspondence to: Woel-Kyu Ha. Research and Development Center, Maeil Dairies Co., Ltd., 63 Jinwiseo-ro Jinwi-myeon, Pyeongtaek 17714, Korea. Tel: +82-31-612-3974, Fax: +82-31-668-0247, woelkyu@naver.com

Received 29 September 2016 Revised 2 January 2017 Accepted 3 January 2017

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/).

Abstract

Milk proteins are composed of casein, further classified into αS1-casein, αS2-casein, β-casein, and κ-casein, and whey protein, which is separated into α-lacatalbumin, β-lactoglobulin, serum albumin, and some minor proteins, such as lactoferrin and immunoglobulin. To reduce the allergenicity of protein, heat treatment and enzymatic protein hydrolysis by endopeptidase are necessarily required. Additionally, membrane technology should be applied to produce a protein hydrolyzate, which has consistent molecular weight of peptide and low in free amino acid without allergenic peptide or protein. Extensive casein hydrolyzate and whey protein hydrolyzate are used for protein source of mainly extensively hydrolyzed protein formula (eHF) intended for the treatment of cow's milk allergy. Also, partially hydrolyzed formula (pHF) is developed, which is using a single protein source e.g., whey protein hydrolyzate. The allergenicity of infant formula can be determined according to molecular weight profile and antigenicity reduction compared to intact protein. More than 90% peptides are present in eHF have a molecular weight of <3,000 Da. Peptide molecular weight profiles of pHF range mainly between 3,000 and 10,000 Da, but have a small percentage of >10,000 Da. Generally, antigenicity reduction in eHF and pHF is 10^-6 and 10^-3, respectively. Even if protein hydrolyzate is manufactured under strict quality control, there is still a risk of cross contamination of allergenic milk components through environmental conditions and the shared manufacturing process. Thus, quality assessment of protein hydrolyzate formula must be performed routinely.

Keywords: Major milk allergen, Enzymatic hydrolysis, Antigenicity, Allergenicity, Hypoallergenic infant formula

Figures and Tables

Fig. 1

Peptide chain length of global commercial partial and extensive protein hydrolysate formula. pWPH, partial whey protein hydrolysate; eCNH, extensive casein hydrolysate; eWPH, extensive whey protein hydrolysate; Da, Dalton.

Table 1

Structural properties of antigenic milk proteins

Properties of protein	Casein				Whey protein
Properties of protein	αS1-casein	αS2-casein	β-casein	κ-casein	β-lactoglobulin	α-lactalbumin	Serum albumin	Lactoferrin
Concentration in milk (g/L)	12–15	3–4	9–11	2–4	3–4	0.6–1.5	0.4	Trace
Molecular weight (Da)	23.6	25.2	24	19	18.3	14	66	80
No. of amino acid residues/molecule	199	207	209	169	162	123	582	703
No. of S-S bridge residues/molecule	0	1	0	1	2 (1 free SH)	4	17 (1 free SH)	16
No. of phosphate residues/molecule	8 (9)	10–13	5	1	0	0	0	0
Isoelectric point	4.9–5	5.2–5.4	5.1–5.4	5.4–5.6	5.3	5	4.9–5.1	8.7
Secondary structure (%) of total chain
α–helix	5–10	?	10	23	10–15	26	34	?
β-sheet	4–15	?	13	31	43	14(β-structure)	50	?
Unordered structure	?	?	77	?	47	60	?	?
Antigenicity	++	++	++	++	+++	++	+	?
Allergen name	Bos d 9	Bos d 10	Bos d 11	Bos d 12	Bos d 5	Bos d 4	Bos d 6	Bos d Lf
Type of Epitope	Sequential	Sequential	Sequential	Sequential	Conformational	Conformational	Conformational	Conformational
Cross reaction to blood serum from CMA baby (%)	60 (total casein)	-	-	-	60–80	50	50	?
Sequence homology human vs. bovine (%)	None human	None human	47	Low	None human	72	80
∑ residues/mole	199	207	209	169	162	123	582
MW/residue per mole	119	122	115	112	113	115	114
∑ lysine, arginine/mole	20	30	15	4	18	12–13	82
Mean MW of tryptic peptide	1,184	842	1,602	4,732	1,017	1,132	809
Mean MW of tryptic and chymotryptic peptide	592	505	829	1,051	654	577	510

CMA, cow's milk allergy; MW, molecular weight; SH, sulfhydryl group.

Table 2

Sequential IgE-binding epitopes in caseins and whey proteins

Milk proteins	IgE-binding sequential epitope (No. of amino acid sequence)	Techniques	Reference
αS1-casein	17–36, 39–48, 69–78, 83–102, 109–120, 123–132, 139–154, 159–174, 173–194	SPOT membrane and microarray	85
αS1-casein	1–31, 65–100, 134–167	Microarray	29
αS1-casein	31–44, 43–56, 83–100, 93–108, 105–114, 117–128, 143–158, 157–172, 165–188, 191–200	SPOT membrane and microarray	86
αS1-casein	1–20, 13–32, 67–86, 181–207	Microarray	87
β-casein	1–16, 45–54, 55–70, 83–92, 107–120, 135–144, 149–164, 167–184, 185–208	SPOT membrane and microarray	88
β-casein	25–50, 52–74, 154–173	Microarray	87
κ-casein	9–26, 21–44, 47–68, 67–78, 95–116, 111–126, 137–148, 149–166	SPOT membrane and microarray	85
κ-casein	34–53	Microarray	87
α-lactalbumin	1–16, 13–26, 47–58, 93–102	SPOT membrane	89
α-lactalbumin	1–19, 15–34, 105–123, 45–64, 60–79, 90–109	Microarray	90
β-lactoglobulin	1–16, 31–48, 47–60, 67–78, 75–86, 127–144, 141–152	SPOT membrane and microarray	89
β-lactoglobulin	58–77	Microarray	87

Table 3

Properties of extensively hydrolyzed protein formula

	Brand name
	Alfare	Alimentum	MA-1	Pepti junior	Pregestimil	Maeil HA	Nutramigen
Manufacturer	Nestle	Ross	Morinaga	Nutricia	Mead Johnson	Maeil Dairies	Mead Johnson
Reconstitution (g/100 mL)	15	Liquid	15	13.1	15	14	15
Energy (kcal/100 mL)	72	67.6	70.1	66	67	64.5	67
Protein (g/100 kcal)	3.5	2.73	3.4	2.8	2.8	2.8	2.8
Fat (g/100 kcal)	5	5.5	3.9	5.6	4	3.9	3.9
Carbohydrate (g/100 kcal)	10.8	10.2	12.9	10.2	13.5	13.4	13
Protein source	WPH	CNH	CNH	WPH	CNH	CNH	CNH
Amino acid added	None	Cys, Tyr, Trp	Tau	None	Tyr, Cys, Trp, Car, Tau	Cys, Tyr, Trp, Tau	Tyr, Trp, Cys
Carbohydrate total (g)	10.8	10.2	12.9	10.2	13.5	10.2	13
Sucrose (g)	None	6.7	1.1	None	None	?	None
Dextrine and starch (g)	10.6	3.3	11.8	10	13.5	?	13
Fat total (g)	5	5.5	3.9	5.6	4	3.9	3.9
MCT oil (g)	2.4	2.8	None	2.8	1	?	0
Linoleic acid (mg)	540	1,600	1,070	1,360	1,300	1,946	2,200
Osmolarity (mosmol/L)	200	300	?	190	310	240	245
Hydrolysis enzyme	Trypsin	Pancreatic enzyme	Animal & microbial enzyme	Trypsin, chymotrypsin	?	Pancreatic Ez, microbial Ez	?

WPH, whey protein hydrolysate; CNH, casein hydrolysate; Cys, cysteine; Tyr, tyrosine; Trp, tryptophan; Tau, taurine; Car, carnitine; MCT, medium chain triglyceride; Ez, enzyme.

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