Investing in Infinimmune

This past December, Pear VC was proud to invest in Infinimmune’s $12M seed round. Infinimmune is reinventing antibody drug discovery by focusing solely on human-derived antibody drugs and mining the insights uniquely gathered from deep characterization of the functional antibody repertoire. Here, we reflect on the broader field of antibody-based therapeutics and why we are excited about Infinimmune’s team, technical approach, and vision.

Antibody drugs have made an undeniable impact on modern medicine. 

Since the FDA’s first approval of a therapeutic monoclonal antibody in 1986, more than 160 marketed antibody drugs have been developed to treat various ailments including cancer,  autoimmune disease, infectious disease, and more.

Seven of the top 20 best-selling drugs of 2022 were antibodies, including Humira, Keytruda, and Dupixent. Collectively, antibody sales that year likely topped $200B, roughly on par with the sales of Apple’s iPhone.

Antibodies play a central defensive role in the adaptive immune system. Recent decades have witnessed tremendous, hard-won advances in the science of these amazing molecular machines and in their application as research tools, diagnostic reagents, and therapeutics. 

Scientists have deciphered their molecular structures; decoded many of the intricate genetic and cellular processes that create and select functional antibodies; devised a variety of sophisticated approaches to identify novel antibodies that effectively bind a given antigen; and developed the tools and processes to reliably characterize, manufacture, and distribute them at scale. 

Newer therapeutic modalities that rely on antibodies or components of them for their function, such as antibody-drug conjugates, targeted radioligand therapies, bispecific T cell engagers, and CAR-T cells, have become established drug classes in their own right. And in recent years, in silico design techniques, aided by ML/AI, have been used to engineer antibodies with better binding, stability, and expression.

Despite all of this progress, our state of understanding regarding the vast diversity of the antibody repertoire actually produced in humans remains shockingly low.

Limitations in the characterization techniques previously applied to this diversity, estimated at 10^11 to 10^18 unique protein sequences in humans, have stymied efforts to fully understand and gain insights from it. Even the advent of next-generation sequencing has not deeply impacted this space—most studies of the antibody repertoire still rely on bulk sequencing technologies, which only capture half of most of the variable region of one antibody transcript at a time.

Why does this matter in antibody drug discovery? 

Because every day, inside every human, the body conducts the equivalent of 100 billion antibody clinical trials, testing each antibody for safety and efficacy in parallel. And these techniques have been developed and optimized over 500 million years of evolution of the adaptive immune system. 

For instance, by studying the immune reactivity of blood samples donated from adults living in a malaria-endemic region, researchers were able to identify broadly reactive antibodies that exhibited non-canonical features (Tan et al., Nature 529:105-109, 2016). These antibodies were found to contain a large insert of an extracellular LAIR1 domain located between key antibody segments. This domain, which is non-canonical and which was not observed in narrowly reactive antibodies, increased binding to malaria-infected red blood cells. These results demonstrated a novel mechanism of antibody diversification that the human immune system can use to create therapeutically effective antibodies.

Clearly, human B cells produce antibodies that mouse B cells and humanized mouse B cells do not. However, the most common methods for discovering therapeutic antibodies today rely on screening antibodies produced in transgenic mice that have been immunized with the desired target antigen, or panning for binding to the antigen in relatively shallow pools of engineered human antibody-like binders expressed via phage or yeast display. 

These approaches are not capable of leveraging the unique insights that can be captured by studying functional antibodies produced by the human immune system.

Enter Infinimmune.

Infinimmune is a startup that is reinventing antibody drug discovery by focusing solely on human-derived antibody drugs. 

Infinimmune was founded by Wyatt McDonnell, David Jaffe, Katie Pfeiffer, Lance Hepler, and Mike Gibbons, a multidisciplinary team of scientists and technologists. These founders have deep expertise in immunology, genomics, computational biology, single cell sequencing, and data analysis, and they take a first principles approach to therapeutics platform development as drawn from previous experiences at 10x Genomics, Pacific Biosciences, and the Broad Institute.

As an example of this expertise, Wyatt, David, and Lance co-authored a paper in Nature last year that discovered a new property of functional antibodies coined light chain coherence (Jaffe et al., Nature 611:352-357, 2022). In this work, the authors used single-cell RNA sequencing to determine the paired heavy and light chain antibody sequences from 1.6 million B cells from four unrelated humans and incorporated a total of 2.2 million B cells from 30 humans.

They compared antibody sequences from pairs of B cells that were isolated from different donors and which shared similar heavy chain segments, specifically, the same heavy chain V gene, and the same amino acid sequence for a key antigen-binding region called CDRH3. [Note: an antibody is composed of a pair of one heavy chain and one light chain that are generated through a process of sequential gene recombination involving V, D (for heavy chains), J, and C segments.]

The authors found evidence of previously unrecognized determinism in the light chain segment (i.e. light chain V gene) used in functional antibodies, which were derived from memory B cells, as opposed to naive antibodies. The discovery of light chain coherence suggests that the sequence space for the light chain of a functional antibody, which has undergone selection by the human immune system to be useful, safe, and effective, is more restricted than what was previously believed. It also carries important implications for the design of therapeutic antibodies, transgenic platforms, and diversification strategies of antibody drugs.

With these types of capabilities and insights at hand, Infinimmune is developing an end-to-end platform to deliver antibody drugs derived directly from the human immune system. 

These truly human antibodies are designed to drug new targets with improved safety and efficacy. Infinimmune is building its own pipeline of drug candidates while also aiming to partner with pharma companies to expand treatment options and reach more patients.

This past December, we were proud to co-invest alongside our friends at Playground Global, Civilization Ventures, and Axial in Infinimmune’s $12M seed round. We are delighted to work closely with the Infinimmune team, and we look forward to sharing many exciting updates to come. Infinimmune’s new HQ is in Alameda, and their team is always interested in hearing from smart, curious, and passionate scientists with a track record of innovation and building things from scratch. If you want to build better drugs for humans, from humans, you can reach the founders directly at founders@infinimmune.com or careers@infinimmune.com—there’s no better way to get in the hiring queue before more job postings go live in 2023!