Nobel laureate Jennifer Doudna, PhD, of University of California, Berkeley

Caribou Biosciences, the developer of gene-edited cell therapies co-founded by Nobel laureate Jennifer Doudna, PhD, has raised $115 million in Series C financing—capital that the company plans to use toward developing its CRISPR-based platform, building its pipeline of oncology treatments, and growing its staff and operations.

How much did Doudna’s 2020 Nobel Prize in Chemistry shared with Emmanuelle Charpentier, PhD, (Max Planck Institute) for pioneering research into CRISPR gene editing sway investors?

“I’m sure that can’t hurt!” observed Caribou co-founder and CEO Rachel Haurwitz, PhD, who studied biology and CRISPR at Doudna’s lab at University of California, Berkeley, as a graduate student from 2008-2012—and who was among GEN’s “Top 10 Under 40” in 2017. “We’re obviously extremely excited for the well-deserved recognition that Jennifer has received.”

Another factor also appears to have warmed investors to Caribou: The genome-edited therapy field has drawn positive attention in recent months since another developer, CRISPR Therapeutics, published positive clinical data about the lead candidate it is co-developing with Vertex Pharmaceuticals, CTX001.

In December 2020, researchers from CRISPR Therapeutics, Vertex, and clinical partners published data in The New England Journal of Medicine from a pair of Phase I/II trials showing continued positive results for the first two patients treated with the CRISPR-Cas9 gene-edited therapy CTX001 and followed for at least a year. According to the data, first announced by the companies in December, one of the patients was treated with CTX001 for transfusion-dependent β-thalassemia (TDT) in the CLIMB-111 trial (NCT03655678), while the other – Victoria Gray — was treated for sickle-cell disease (SCD) in the CLIMB-121 trial (NCT03745287). The researchers also reported positive results after administering CTX001 to another eight patients (six with TDT and two with SCD).

“In general, this is an exciting moment for genome editing in the cell therapy space,” Haurwitz said. “We’ve seen a handful of developers demonstrate early safety, and hence potential efficacy, so we see a lot of opportunity for Caribou to bring our programs that really have additional capabilities and advantages into the clinic, and we believe that our programs hold best-in-class potential for their targets.”

Three of Caribou’s four announced pipeline programs are allogeneic genome-edited chimeric antigen receptor T-cell (CAR-T) therapies, led by its sole clinical-phase candidate CB-010, which targets CD19 and has PD-1 deleted by CRISPR genome editing. CB-010 is being evaluated in a Phase I trial (NCT04637763) in patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL).

Initial Data Expected at ASH

Haurwitz said Caribou expects to release initial data from the trial at the American Society of Hematology (ASH)’s 63rd annual conference, set for December 11-14 both in Atlanta and virtually.

During the first half of 2022, Caribou expects to file an IND for its preclinical, second genome-edited CAR-T candidate CB-011, which targets BCMA-positive tumors and is being developed for the treatment of relapsed/refractory multiple myeloma. According to Caribou, CB-011 is immunologically cloaked for enhanced persistence.

“The idea is to manipulate HLA class I [antigen] presentation in order to prevent the patient’s immune system from rapidly clearing the therapy,” Haurwitz explained.

Caribou does that for CB-011 in two ways. It uses genome editing to get rid of the protein beta-2 microglobulin (beta-2-M), in order to completely wipe out all class i presentation from the surface of the CAR-T. The second step is then to site specifically insert a fusion protein, beta-2-M with the antigen HLA-E, in order to prevent both the patient’s T cells and their natural killer cells from rapidly clearing the therapy.

Allogeneic cell therapies run the risk of recognition as foreign by patients’ immune systems, which then set out to kill the cell product fairly rapidly.

“By immune cloaking it, we allow the CB-011 CAR-T product to persist for a longer period of time, thereby buying additional time for additional anti-tumor activity,” Haurwitz said. “To the best of our knowledge, we’ll be the first group to use that type of immune cloaking strategy in the clinic.”

Caribou is also developing a third allogeneic CAR-T cell therapy, CB-012, which targets CD371 for the treatment of relapsed/refractory acute myeloid leukemia. CB-012 uses fully human single-chain variable fragment (scFv) binders for CD371 that the company has exclusively in-licensed from Memorial Sloan Kettering Cancer Center (MSK), under an agreement announced in November 2020 and whose value was not disclosed.

The anti-CD371 scFvs were developed in the lab of Renier Brentjens, MD, PhD at MSK in collaboration with the Tri-Institutional Therapeutic Discovery Institute (Tri-I TDI). Tri-I TDI is a nonprofit drug discovery company wholly owned by MSK, Weill Cornell Medicine, and The Rockefeller University. MSK has the sole responsibility for licensing these scFvs and related intellectual property for commercialization.

“As early as towards the end of next year, we would be in a position to file an IND,” Haurwitz said.

Serving Chardonnay

CB-010, ‘011, and ‘012 are complex immune cell therapies all based on Caribou’s CRISPR hybrid RNA-DNA (chRDNA) guide technology—which the Bay Area company cutely pronounces “Chardonnay.” CB-010 uses chRDNA that incorporates the Cas9 enzyme, while ‘011 and all other Caribou programs use Cas12a.

ChRDNAs are highly specific RNA-DNA hybrid guides that according to the company direct substantially more precise genome editing than all-RNA guides by driving highly specific, multiplex genome editing, including gene insertion. The hybrid guides are designed to address the challenge of all-DNA guides, which fail to support editing activity, and all-RNA guides, which lead to both on- and off-target editing.

chRDNAs lead to more specific genome editing because they decrease the affinity of the CRISPR complex for the target DNA, Haurwitz said.

“That might sound counterintuitive initially. I think our gut reaction might be that higher affinity is better. However, it turns out that the genome really represents a never-ending laundry list of potential target sites, both the on-target site and many potential off-target sites. So we actually want to de-tune the affinity of either Cas9 or Cas12a for its targets,” Haurwitz said.

“By reducing the affinity, we’re still able to get appropriate high efficiency on target editing. But we dramatically reduce the risk of the CRISPR complex editing the wrong site in the genome.”

Also in Caribou’s pipeline is a program to develop iPSC-derived allogeneic natural killer (NK) cell therapies—which the company calls iNK cell therapies—for solid tumor indications. The lead candidate in that program, CB-020, is a preclinical iNK cell therapy with an undisclosed target. The first IND is a few years away, Haurwitz says.

Equity, No Update from AbbVie

Caribou’s Series C financing was co-led by three new investors specializing in healthcare funding: Farallon Capital Management, PFM Health Sciences, and Ridgeback Capital Investments. Santhosh Palani, Ph.D., Partner at PFM Health Sciences, and Jeffrey Long-McGie, Managing Director at Ridgeback Capital Investments, were named to Caribou’s Board of Directors.

Among investors participating in the Series C financing was AbbVie Ventures, AbbVie’s corporate strategic venture capital arm. AbbVie’s capital is an undisclosed portion of the $40 million combined upfront cash and equity investment that the biopharma giant committed to Caribou in its up-to-$340 million CAR-T therapy collaboration launched last month.

In return, AbbVie gained exclusive rights to Caribou’s next-generation Cas12a chRDNA genome editing and cell therapy technologies to develop two CAR-T cell cancer therapies against undisclosed targets. Under their collaboration, AbbVie has the option to pay a fee, also undisclosed, to expand the collaboration to include up to two more CAR-T cell therapies.

AbbVie and Caribou have not revealed a timeframe for advancing collaboration candidates into clinical trials. Haurwitz would not offer an update on the collaboration beyond the companies’ initial announcement.

Joining AbbVie as new investors in the Series C financing were Adage Capital Partners, Avego Bioscience Capital, Avidity Partners, Invus, Janus Henderson Investors, LifeSci Venture Partners, The Leukemia & Lymphoma Society Therapy Acceleration Program® (LLS TAP), Monashee Investment Management, Point72, and funds managed by Tekla Capital Management.

Existing investors participating in the round included Heritage Medical Systems, Maverick Ventures, and Pontifax Global Food and Agriculture Technology Fund (Pontifax AgTech).

Powerful Engine

The new financing brings to $157 million the total capital that Haurwitz and Caribou have raised since it was established in 2011 by Haurwitz, Doudna, and Martin Jínek, PhD, a former postdoctoral fellow in Doudna’s lab, now at the University of Zurich, who led the seminal 2012 study leading to the Nobel Prize.

Also that year, the company became operational, which would make Caribou the oldest CRISPR therapeutics company as far as Haurwitz knows. Caribou’s aim is to commercialize applications based on the nucleic acid modification capabilities found in prokaryotic CRISPR systems.

In 2007, Rodolphe Barrangou, PhD, a former Chairman of Caribou and onetime scientific advisor to the company, led the group that characterized CRISPR systems as a form of prokaryotic adaptive immunity that provides a critical line of defense against invading phages. (Barrangou is the Todd R. Klaenhammer Distinguished Professor at North Carolina State University and Editor-in-Chief of The CRISPR Journal, published by GEN publisher Mary Ann Liebert, Inc.)

Caribou raised $11 million in Series A financing in 2015, and $30 million in a Series B round the following year. The company has also raised an undisclosed amount of additional non-dilutive funding.

Caribou is growing, now at 65 staff, and should continue that trajectory using proceeds of the financing.

“Caribou has successfully leveraged its next-generation CRISPR technology platform to create a promising clinical-stage therapeutic and a pipeline of pre-clinical allogeneic CAR-T and CAR-NK cell therapies that are potentially transformative for patients with unmet medical needs,” Doudna said in a statement released by Caribou.

“Given its pioneering and selective approach in the field, Caribou’s CRISPR technology platform should continue to serve as a powerful engine for therapeutic development.”

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