A little more than three months after it raised $115 million in a Series C financing round, Caribou Biosciences late last week filed for an initial public offering whose size has not yet been determined, though the company’s S-1 registration statement filed with the U.S. Securities and Exchange Commission, included a placeholder amount of $100 million.

The company plans to trade its shares on the NASDAQ Global Select Market, under the symbol CRBU.

Caribou was established in 2011 by Haurwitz, Doudna, Martin Jínek, 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, and James Berger, professor in the department of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine.

That year, Caribou also became operational, which would make it the oldest CRISPR therapeutics company as far as Haurwitz recalled earlier this year. Caribou’s aim is to commercialize applications based on the nucleic acid modification capabilities found in prokaryotic CRISPR systems.

“We believe that our technology has broad potential to generate gene and cell therapies in oncology and in therapeutic areas beyond oncology, including immune cell therapies, cell therapies derived from genome-edited iPSCs, and in vivo genome-editing therapies,” Caribou stated in its IPO filing.

Caribou’s statement listed four planned uses for proceeds from the IPO. One is advancing the clinical development of the company’s sole clinical-phase candidate CB-010, which targets CD19 and has PD-1 deleted by CRISPR genome editing. CB-010 is being evaluated in the Phase I ANTLER trial (NCT04637763) in patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL), with initial data from the study expected in 2022.

Enhanced persistence

A second use of IPO proceeds, Caribou stated, will be funding IND-enabling activities and potential launch of clinical studies for two of its other candidates, CB-011 and CB-012.

CB-011, Caribou’s second genome-edited CAR-T candidate, targets BCMA-positive tumors and is being developed for the treatment of relapsed/refractory multiple myeloma. According to Caribou, CB-011 is immunologically cloaked in order to prevent the patient’s immune system from rapidly clearing the therapy, since 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.

Caribou achieves that enhanced persistence 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.

Caribou expects to file an IND for CB-011 next year.

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. The company expects to file an IND for CB-012 in 2023.

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.

CRISPR hybrid RNA-DNA

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 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.

The genome-editing technologies currently used in the allogeneic cell therapy field generally have limited efficiency, specificity, and versatility for performing the multiple, precise genomic edits necessary to address insufficient persistence,” Caribou stated in its IPO. “Our chRDNA technology is designed to address these genome-editing limitations and improve cell therapy activity. By applying this approach to allogeneic cell therapies, we believe we can unlock their full potential by improving upon their effectiveness and durability.”

chRDNAs lead to more specific genome editing because they decrease the affinity of the CRISPR complex for the target DNA, Haurwitz told GEN Edge in March, shortly after Caribou completed its $115 million Series C convertible preferred stock financing, which generated for the company net proceeds of $108.8 million.

Among investors participating in the Series C was AbbVie Ventures, AbbVie’s corporate strategic venture capital arm. AbbVie committed $40 million in combined upfront cash and equity investment in its up-to-$340 million CAR-T therapy collaboration launched in February.

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.

“We view this collaboration as an external recognition of the potential for our chRDNA genome-editing technology to significantly improve genome-editing specificity and efficiency,” Caribou stated in its IPO filing.

According to the IPO filing, Caribou has received $30 million in upfront cash from AbbVie—part of approximately $311.2 million in net proceeds from equity financings and contract revenues received by Caribou. The figure includes approximately $150.1 million in net proceeds from equity investments; and approximately $88.4 million in net proceeds from the sale of Intellia Therapeutics common stock received under Caribou’s CRISPR-Cas9 license agreement with Intellia.

Written in iNK

Caribou also said it plans to set aside some proceeds from the IPO toward continuing research and development of its program to develop iPSC-derived allogeneic natural killer (NK) cell therapies—which the company calls iNK cell therapies—for multiple solid tumor indications. The lead candidate in that program, CB-020, is a preclinical iNK cell therapy, for which Caribou said it expects to select a cell-surface target in 2022.

“We have not yet chosen which genome-editing technology we will use to edit the iNK cells nor do we know whether such editing will be successful,” Caribou disclosed. “To date, we have focused on Cas12a chRDNA editing of iPSCs and on differentiating iPSCs into iNKs.”

Caribou’s filing also cited several other additional potential uses for IPO proceeds, including:

• Advancement of Caribou’s genome-editing technologies
• Discovery-stage research toward potential additional programs
• Working capital and other general corporate purposes, including the additional costs associated with being a public company

Based in Berkeley, CA, Caribou has a staff of more than 65 employees and licensing and collaboration revenue that more than doubled last year to $12.361 million from $5.788 million in 2019. For the first quarter of this year, license and collaboration revenue dipped to $1.586 million from $1.701 million in Q1 2020.

However, Caribou has also seen a year-over-year increase in net operating losses, to $36.1 million last year from $34.3 million in 2019. This year, Caribou finished the first quarter with a net operating loss of $13.2 million, up from a net operating loss of $9.8 million in Q1 2020.

“We expect to continue to incur significant expenses and operating losses over the next several years and for the foreseeable future as we seek to advance product candidates through preclinical and clinical development, expand our research and development activities, develop new product candidates, complete preclinical studies and clinical trials, seek regulatory approval and, if we receive approval from the [FDA] or foreign regulatory authorities, commercialize our products,” Caribou stated.

BofA Securities, Citigroup Global Markets, and SVB Leerink are acting as joint book-running managers for the IPO.