Since ALS has a protective role on IGFBP‐3, presumably by preventing its degradation by the action of proteases, serum IGFBP‐3 levels are decreased as well.79 Both tumor‐derived and recombinant preparations of various IGF‐IIE isoforms seem to bind to IGFBP‐2, IGFBP‐3, and IGFBP‐5 with an affinity similar to that of mature IGF‐II.40, 80 Besides a shortage of ALS and IGFBP‐3, there is evidence that incorporation of big IGF‐II into 150 kD ternary complex formation is severely impeded. This evidence concerns the gene IGFBP5 and amyotrophic lateral sclerosis.