Thanks, Ian Wilkinson, for adding to the conversation about the importance of human Ig lambda light chains. I wholeheartedly agree about lambda light chains being important for engaging certain epitopes, either altogether or with sufficient affinity to meet potency requirements. I have 20+ years of accumulated anecdotal evidence, first using XenoMouse(R) Mice and now using AlivaMab(R) Mice.
Breaking the chain of command - is it time to give lambda a chance? In humans about 67% of light chains are kappa (κ) and 33% lambda (λ). Yet in therapeutic INNs the proportion of λ drops to about 13%. This is partly due to the fact rodents only have 1-5% λ LCs, meaning hybridoma derived mAbs are almost always κ. Early phage libraries and transgenic mice then followed this bias. There was a great LI discussion on this the other week. λ mAbs also have a reputation as being undevelopable. This perception and the historic discovery bias has created an underrepresentation of λ mAbs. But are we missing something here? Some species have a very heavy bias to one LC type or the other: rodents are >95% κ whereas sheep, cows and horse are almost exclusively λ. Humans, rabbits and pigs evolved with a slightly more even mix, surely something is driving this? An increasing number of reports point towards a link between VL germline and function with λ mAbs preferentially engaging certain epitopes, suggesting a potential functional cost to neglecting λ mAbs entirely. So, can we solve the developability problems; are they really that bad? A recent study using the Therapeutic Antibody Profiler tool suggests that although λ mAbs are on average less developable than κ, a sizeable proportion have low-risk profiles and could easily be selected for or engineered. More interesting than that is an Eli Lilly study from 2013 that only has 18 citations. They propose that much of the developability concerns with λ are due to the disulphide bond between LC and HC being more prone to cleavage, making the full IgG less stable under reducing conditions. In κ LCs the sequence ends EC, in λ it ends ECS. The demonstrate that by removing the serine from the end of the λ LC you get a far more stable IgG. Then they show that the serine deleted λ-IgG has about a 6-fold increase in ADCC! Presumably the serine interferes with interaction of Fc receptors in the hinge and upper CH2. Is this widely known? I only see one antibody (opucolimab) with a Ser deleted λ and this isn’t even an Eli Lilly mAb. Is the ADCC enhanced version of a λ LC more or less potent than κ? They didn’t look in the paper but it would be interesting to understand. What is the role of the Serine in λ, it must be there for a reason? Is this like the C-terminal lysine on the HC or something completely different? Are lambdas a naturally 'silent' LC, a bit like IgG4 for HCs? Lots of questions, no real answers. See first comment for links to various publications. ----- I'm Ian, I post about antibody engineering, recombinant proteins and my journey to bootstrap Gamma Proteins into a leading supplier of Fc receptors. If you like my content please reshare with your network and follow me to see more.