Nowhere in biopharma does the adage, “Follow the money” better apply, perhaps, than immuno-oncology, whose market size is expected to balloon to $19 billion in 2019 and $34 billion in 2024 (GlobalData).

With a combined roughly $2.5 billion in sales last year, drugs that harness the body’s immune system as a weapon against cancer have already begun to generate billions. Bristol-Myers Squibb (BMS) immuno-oncology treatment Yervoy® (ipilimumab) surpassed $1 billion in worldwide revenues last year, with BMS’ Opdivo® (nivolumab) close behind at $942 million. Opdivo has already surpassed that total this year, zooming in January–June to $1.544 billion. And while Yervoy slid 19% to $504 million this year due to competition from Opdivo and Merck & Co.’s Keytruda® (pembrolizumab), the two BMS drugs are expected to generate a combined $7.5 billion in sales by 2022, according to Trefis.

Speaking of Keytruda, its $563 million in the first half of 2016 is just $3 million shy of what the drug made all of last year. And Keytruda is expected to leap to $7 billion in sales by 2024 (Research and Markets).

With the potential for billions in new revenues, biopharma giants have proven willing to shell out billions in collaborations with smaller biotechs aimed at developing new immunotherapies for cancer. Earlier this year, the Tufts Center for the Study of Drug Development reported that more than 130 biotechs and 20 pharmaceutical companies were working on immuno-oncology therapies, with the number of collaborations rising to 58 last year from six in 2013.

The largest of these—and several others that were launched this year—can be found in GEN’s list of top 15 immuno-oncology collaborations below. The alliances are ranked by dollar value as disclosed by the companies in regulatory filings, press announcements, and other public statements. Each collaboration is listed by partner names, value, and date announced, followed by a summary, and updates provided by the companies since their launch announcements.

Interestingly, the total value of all 15 ranked collaborations is approximately $30 billion. It’s also fair to say, for now, that the pace of billion-dollar-plus partnership activity is rising, as 2016 has already seen five such collaborations, compared to six last year and four in 2014. However, the list does not include collaborations where details were not disclosed. For example, Novartis and Xencor only revealed the $150 million upfront portion of their partnership to develop bispecific antibodies, announced June 28.

#15. Celgene and Juno Therapeutics

Value: Approximately $1 billion for Juno, including approximately $150 million upfront

Date Announced: June 29, 2015

Summary: 10-year global collaboration to develop and commercialize cancer and autoimmune diseases immunotherapies, with an initial focus on chimeric antigen receptor (CAR) technology and T-cell receptor (TCR) technologies. Celgene has the option to serve as commercialization partner for Juno’s oncology and cell therapy autoimmune product candidates, including Juno’s CD19- and CD22-directed CAR T-cell product candidates.

Updates: On April 28 in announcing first-quarter results, Celgene disclosed that during that month, it exercised its option to develop and commercialize Juno’s CD19 program outside North America and China. The companies agreed to share global development expenses for products in the CD19 program. Celgene agreed to pay Juno a royalty at a percentage in the mid-teens on any future net sales of therapeutic products developed through the CD19 program in Celgene’s territories. Celgene entered into a prenegotiated license agreement, with Juno by paying $50 million for the license, Celgene disclosed recently.

#14. Celgene and Agios Pharmaceuticals

Value: About $1 billion-plus for Agios, including $200 million upfront

Date Announced: May 17, 2016

Summary: Companies agreed to partner to discover, develop, and commercialize metabolic immuno-oncology therapies, based on Agios’ cellular metabolism research platform. Agios agreed to lead exploratory research, drug discovery, and early development efforts.

Updates: In a July report, Celgene said the collaboration’s initial 4-year term will expire in May 2020, adding: “We may extend the term for up to two additional 1-year terms or in specified cases, up to 4 additional years.” At the end of the research term, Agios said “Celgene may designate for continued development up to three research programs for which development candidates have yet to be nominated, which are referred to as continuation programs.” Agios said it may conduct further research and preclinical and clinical development activities on any continuation program, at its expense, “through completion of an initial Phase I dose-escalation study.”

#13. Eli Lilly and Innovent Biologics

Value: More than $1 billion, including $56 million upfront

Date Announced: October 11, 2015

Summary: In expansion of up-to-$456 million cancer therapy strategic alliance announced March 20, 2015, companies agreed to support development and potential commercialization of up to three anti-programmed cell death-1 (PD-1)-based bispecific antibodies for cancer treatments over the next decade, both inside and outside of China. Lilly agreed to exercise rights from the earlier agreement to develop, manufacture, and commercialize these potential cancer treatments outside of China, while Innovent won rights to develop, manufacture, and commercialize the treatments for China, subject to a Lilly opt-in right for co-development and commercialization.

Updates: No subsequent announcements.

#12. Celgene and Sutro Biopharma

Value: More than $1 billion-plus for Sutro, including $95 million upfront (a sum that includes an unspecified equity investment)

Date Announced: October 23, 2014

Summary: Companies agreed to advance into immuno-oncology, in expansion of a nearly 2-year-old cancer collaboration originally intended to discover and develop multispecific antibodies and antibody–drug conjugates (ADCs). Expansion doubled the value of the partnership, which was refocused on established immuno-oncology targets such as programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), as well as new undisclosed targets, using Sutro’s Xpress CF™ and Xpress CF+™ cell-free biologics development platforms. After the initial period, Celgene was given exclusive option to acquire Sutro.

Updates: No subsequent announcements.

#11. Roche and Blueprint Medicines

Value: Up to $1.01 billion for Blueprint, including $45 million upfront

Date Announced: March 15, 2016

Summary: Companies agreed to discover, develop, and commercialize up to five small-molecule therapeutics targeting kinases deemed important in cancer immunotherapy. The five could be either single products or products to be combined with Roche therapeutics. Roche will hold options triggered upon achievement of Phase I proof-of-concept for an exclusive license to each drug candidate developed under the collaboration.

Updates: In August, Blueprint disclosed that the partners “have identified targets for three of the collaboration programs, two of which began in the first half of 2016 and the third of which is expected to begin in 2016, and the parties have agreed to work together to use the company’s novel target discovery engine and proprietary compound library to select targets for up to two additional collaboration programs.”

#10. Bristol-Myers Squibb (BMS) and CytomX Therapeutics

Value: Up to $1.242 billion for CytomX, including $50 million upfront

Date Announced: May 27, 2014

Summary: Companies agreed to discover, develop, and commercialize new immunotherapies against multiple cancer immunotherapy targets, using CytomX’s Probody™ drug discovery platform. CytomX agreed to grant BMS exclusive worldwide rights to develop and commercialize Probody therapeutics designed to bind selectively to tumors for up to four oncology targets, including the immune inhibitory checkpoint receptor cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). BMS will have additional rights to substitute up to two collaboration targets.

Updates: On January 20, CytomX disclosed its receipt of a $10 million milestone payment from BMS following its selection of a third target in the companies’ strategic oncology collaboration.

#9. Sanofi and BioNTech

Value: Up to $1.5 billion-plus for BioNTech, including $60 million upfront

Date Announced: November 3, 2015

Summary: Companies agreed to discover and develop up to five cancer immunotherapies, each consisting of a mixture of synthetic messenger RNAs (mRNAs), using BioNTech’s mRNA formulation technology. BioNTech will also supply part of the mRNA material needed for development activities from its in-house GMP manufacturing unit. BioNTech has the option to co-develop and co-commercialize two of the five mRNA therapeutics products with Sanofi in the EU and the U.S.

Update: No subsequent announcements.

#8. Baxalta and Symphogen

Value: Up to €1.4 billion (approximately $1.6 billion) for Symphogen

Date Announced: January 4, 2016

Summary: Companies agreed to develop Symphogen’s portfolio of early-stage immuno-oncology programs, including new treatments against six undisclosed checkpoint targets, with the first program to enter clinical studies in 2017.

Update: On June 3, Baxalta became an indirect wholly owned subsidiary of Shire following completion of the companies’ $32 billion merger. Symphogen CFO and Deputy CEO Martin Olin told GEN that the collaboration is still in effect.

#7. Baxalta and Precision BioSciences

Value: Up to $1.7 billion for Precision, including $105 million upfront

Date Announced: February 25, 2016

Summary: Companies agreed to develop allogeneic chimeric antigen receptor (CAR) T-cell therapies, by bringing together Baxalta’s immuno-oncology candidates with Precision’s ARCUS genome editing platform technology. Baxalta and Precision agreed to develop CAR T-cell therapies for up to six undisclosed targets, with the first program expected to enter clinical studies in late 2017. Companies said the CAR T-cell therapies will address areas of major unmet need in multiple unspecified cancers.

Update: On June 3, Baxalta became an indirect wholly owned subsidiary of Shire following completion of the companies’ $32 billion merger.

#6. Bristol-Myers Squibb (BMS) and Five Prime Therapeutics

Value: Up to $1.74 billion for Five Prime, including $350 million upfront

Date Announced: October 15, 2015

Summary: BMS agreed to co-develop and co-commercialize Five Prime’s colony-stimulating factor 1 receptor (CSF1R) antibody program, led by the Phase I cancer/immunology compound cabiralizumab (FPA008). BMS agreed to oversee development and manufacturing of cabiralizumab for all indications, subject to an option by Five Prime to conduct and pay for future studies to support approval of cabiralizumab in pigmented villonodular synovitis (PVNS) and cabiralizumab in combination with Five Prime’s internal pipeline assets in immuno-oncology.

Update: On May 12, Five Prime said cabiralizumab was advanced into the Phase II dose-expansion portion of the ongoing Phase I/II trial in PVNS. Cabiralizumab was granted the FDA’s Orphan Drug Designation for PVNS in January 2016.

#5. Sanofi and Regeneron

Value: Up to $2.17 billion for Regeneron, including $640 million upfront

Date Announced: July 28, 2015

Summary: Sanofi and Regeneron agreed to jointly develop REGN2810, a programmed cell death protein 1 (PD-1) inhibitor currently in Phase I and launch clinical trials in 2016 with new therapeutic candidates based on ongoing preclinical programs. The partners committed to spend $325 million each toward developing REGN2810.

Update: In releasing second-quarter results August 4, Regeneron said REGN2810 had entered a potentially pivotal clinical study for the treatment of advanced cutaneous squamous cell carcinoma during Q2.

#4. Celgene and Jounce Therapeutics

Value: Up to $2.6 billion for Jounce, including $225 million upfront and a $36 million equity investment by Celgene

Date Announced: July 19, 2016

Summary: Celgene received options to develop and commercialize jointly cancer immunotherapies that include Jounce’s lead candidate JTX-2011, a monoclonal antibody expected to enter clinical trials by year’s end, and other cancer immunotherapies. Celgene gained options from Jounce for up to four of its early-stage programs to be selected from a defined pool of B-cell, regulatory T-cell, and tumor-associated macrophage targets emerging from the Jounce Translational Science Platform; also gained was an additional option to share a checkpoint immuno-oncology program equally with Jounce.

Update: In July, Celgene disclosed that the collaboration agreement had an initial term of 4 years, which may be extended up to 3 additional years.

#3. Merck KGaA and Pfizer

Value: Up to $2.85 billion for Merck KGaA, including $895 million upfront

Date Announced: November 17, 2014

Summary: Merck KGaA agreed to jointly develop and commercialize its programmed cell death ligand-1 (PD-L1) checkpoint inhibitor MSB0010718C (since renamed avelumab and also known as PF-06834635) with Pfizer, both as a single agent and in various combinations with the companies’ oncology therapies.

Update: On July 6, the companies said they launched the Phase III JAVELIN Ovarian 100 trial. The trial is intended to assess avelumab in combination with, and/or as follow-on (maintenance) treatment to, platinum-based chemotherapy in patients with locally advanced or metastatic disease (Stage III or Stage IV) with previously untreated epithelial ovarian cancer.

#2. Pfizer and Cellectis

Value: Up to $2.885 billion for Cellectis, including $80 million upfront

Date Announced: June 18, 2014

Summary: Pfizer and Cellectis agreed to develop chimeric antigen receptor (CAR) T-cell cancer immunotherapies directed at select targets using the French biotech’s CAR T-cell platform technology. Pfizer has exclusive rights to develop and commercialize CAR T-cell cancer therapies directed at a total of 15 targets of its choosing. Both companies agreed to work together on preclinical research for four of 12 additional targets to be selected by Cellectis, with Pfizer having the right of first refusal to the four.

Update: On June 20, Cellectis said the first patient was dosed in a Phase I study of UCART19 in pediatric acute B lymphoblastic leukemia. UCART19 is an allogeneic CAR T-cell candidate for CD19-expressing blood malignancies, gene edited with Cellectis’ TALEN® technology.

#1. Merck & Co. and Ablynx

Value: €5.78 billion ($6.4 billion)

Date Announced: July 22, 2015

Summary: In an up-to-€4.08 billion (about $4.5 billion) expansion of an up-to-€1.7 billion ($1.9 billion) immuno-oncology collaboration to address additional checkpoint modulator targets, announced February 3, 2014, the companies agreed to discover and develop up to 12 additional cancer drugs based on single-domain antibody fragments, or Nanobodies®, through preclinical proof-of-concept. After that, Merck will have the option to advance specific lead candidates. Merck will also oversee clinical development, manufacturing, and commercialization of any products resulting from the collaboration, which grew to 17 Nanobodies programs.

Updates: On October 15, 2015, Ablynx said preclinical proof-of-concept was achieved with a bispecific Nanobody program developed through the Merck & Co. collaboration, triggering a €3.5 million ($3.9 million) milestone payment to Ablynx.

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