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Accessing the Untapped Potential of 33% of Human IgG

Harvard economist Michael Porter, PhD offers a clever observation that’s as seemingly apropos to science as it is business: "The essence of strategy is choosing to perform activities differently than rivals do."

Or, in simpler terms, “embracing unconventional thinking can yield unexpected dividends — and a potential competitive advantage.”

We’ve witnessed that philosophy in action firsthand in the research that we do with our clients, especially when it comes to selecting humanized transgenic mouse models for antibody discovery campaigns. Intrinsically predisposing a research campaign toward a single mouse model — or, worse yet, ignoring the value of transgenic platforms altogether — can potentially sacrifice the considerable benefits that alternative approaches can bring to the table.

The Short Course: Pledging Kappa-Lambda-Why?

Beginning with basic biology, the prevalence of immunoglobulin (IgG) light chains classes differs considerably from species to species.

In humans, endogenous circulating antibodies are around two-thirds kappa light chain and about one-third lambda light chain. This differs greatly from the IgG profile of a conventional mouse or rat, which are closer to 95 percent kappa, five percent lambda.

Although roughly 33 percent of natural human IgG features a lambda light chain, of the approximately 100 approved therapeutic monoclonal antibodies (designed to take on everything from cancer and HIV to asthma and osteoporosis), only five feature a lambda light chain. This is perhaps not too surprising, since for the most part a majority of approved therapeutics were originally discovered in immunized rodents expressing mostly kappa light chains.

Thanks to the continued development and increased availability of multiple transgenic animal platforms, today’s researchers can now interrogate something that, up until recently, had been a relatively untapped resource in therapeutic antibody discovery: human lambda light chain producing mice and rats.

Prompting a Stronger Lambda Response

The good news for antibody researchers is that human lambda light chain rodents are available from several well-established providers, including Alloy Therapeutics, Ligand (OmniRat^Ⓡ) and Trianni^Ⓡ At Antibody Solutions, we have (thus far) generated lambda light chain therapeutic antibody candidates with the OmniRat and Trianni platforms, as well as conventional rats.

During that research, we’ve observed that some targets can, surprisingly, drive a predominantly lambda response. Importantly, for these targets, the best candidate antibodies end up being lambda light chain antibodies — not kappa.

In past discovery efforts using conventional rodents, lambda light chain antibodies were so rare that they were considered to be of very little importance. Even in earlier iterations of transgenic human antibody producing mice, the human lambda light chain was not included due to limitations in gene editing technology and overall feasibility. Due to advances in the field it is now possible and available in the latest generation of transgenic animals.

Even with more widespread availability, there’s still work to be done in the development of methods and reagents to maximize the potential of lambda light chain antibodies. In addition to improving methods and optimizing reagents for the characterization, sequencing and purification of lambda light chain antibodies, Antibody Solutions has embraced the promise of lambda-based platforms and has ensured our science and processes are primed to capitalize on their emerging potential.

Despite best efforts and years of experience, unfortunately there’s no practical way to predict whether the best antibody for your target will be lambda or kappa. The optimal approach should include animals that offer both kappa and lambda light chains. In short, the bottom line is this: If you choose to immunize only kappa or only lambda animals, you may miss the best lead therapeutic candidate.

The good news? In most cases, you can advance along both research paths by simply including a few more animals in the earliest stages of discovery. Working with a company like ours (which leverages a data-driven discovery platform to focus resources on what is working and not on what isn't), any additional front-end cost is minimal compared to the potential benefits gained on the back end.

Provisioning for The Road Less Traveled

Maximizing your chances for success in any antibody discovery campaign will require experience and expertise with the fundamental methods and approaches. (That’s been true since the industry was invented a couple decades ago.) But it also compels a willingness to incorporate a wide array of perspectives — including some that may not seem obvious at first — around potential strategies to generate the best possible fit-for-purpose antibodies.

Our transgenic animal page has some useful at-a-glance food for thought, and this poster summarizes our results with four of the leading transgenic platforms. We’d like to hear your thoughts on the potential for lambda chain research with your targets, so connect with us to get the conversation started.

And meanwhile, if incorporating a lambda light chain platform represents a departure for you and your team, draw a little inspiration from a truism in Robert Frost’s oft-cited poem “The Road Not Taken”:

"Two roads diverged in a wood, and I —
I took the one less traveled by,
And that has made all the difference."

— Robert Frost