ICE® (innate cell engager) molecules bring together the innate immune cell (NK cell or macrophage) and tumor cell by binding to the CD16A receptor on innate immune cells and a specific receptor on the tumor cells. Once this bridge is established, the immune cell is activated to release factors that directly kill the tumor cell.
In contrast with other antibody-based therapeutics, ICE® (innate cell engager) molecules generated from the ROCK® (Redirected Optimized Cell Killing) platform avoid competition with the body’s own circulating serum IgG by binding efficiently and stably to a unique epitope on the CD16A receptor on NK cells and macrophages with high affinity and avidity.1,2
Our ICE® (innate cell engager) molecules restore dysregulated NK cells, and increase cytotoxic activity
of healthy donor–derived NK cells 3,4
Innate immune cell reactivation through ICE® (innate cell engager) molecules enables tumor recognition and initiates an immune response. When the NK cell and tumor cell are brought together, the innate immune cell releases perforins to create pores in the tumor cell membrane through which granzymes enter the tumor cell, triggering apoptosis and resulting in tumor cell death.
Acimtamig is Affimed’s first-in-class ICE® (innate cell engager) molecule targeting CD30 on cancer cells and CD16A on innate immune cells. It has shown antitumor activity as monotherapy in a number of clinical trials leading to meaningful results for patients with CD30-positive lymphomas.4, 5, 6
When used in combination with an anti–PD-1 antibody in Hodgkin lymphoma, acimtamig demonstrated promising efficacy, including an ORR of 88% at the highest treatment dose, as well as a CR of 46% (per independent assessment).7 Both ORR and CR rates were higher in combination with acimtamig than with the anti-PD-1 antibody alone. 7
When combined with fresh cord blood-derived natural killer (NK) cells, acimtamig yielded unprecedented results in a phase 1/2a study in heavily pre-treated patients with Hodgkin lymphoma and Non-Hodgkin lymphoma. Patients treated at the recommended Phase 2 dose achieved a 94% ORR rate and a CR rate of 71%. There were no serious adverse events and the treatment was well tolerated.8 Affimed’s new phase 2 study, LuminICE-203, builds on these data and investigates acimtamig in combination with alloNK® an off-the-shelf, allogeneic NK cell from Artiva Biotherapeutics, in patients with r/r classical Hodgkin lymphoma and an exploratory arm in r/r/ PTCL (NCT05883449).
AFM24 is an EGFR-directed ICE® molecule, which exhibits a distinctive mechanism of action that engages innate immune cells by recruiting NK cells and macrophages to the site of the tumor for mediating an effective and efficient anti-tumor response.9 It thereby does not rely on the EGFR signaling pathway, but uses EGFR as a docking site only, which suggests that AFM24 can be used in all EGFR-expressing tumors, including tumors that have become resistant to signaling inhibition. 9
AFM24 is being evaluated in three clinical studies exploring a range of indications: Phase 1/2a data of the monotherapy (NCT04259450) have demonstrated a well-managed safety profile and an activation of NK cells.10, 11 In addition, AFM24 is being evaluated in a Phase 1/2a clinical trial in combination with the checkpoint inhibitor atezolizumab (NCT05109442) and a Phase 1 clinical trial with autologous NK cells (NCT05099549).
Based on the encouraging signals of activity seen in monotherapy, Affimed is focusing the further development of AFM24 as combination therapy with atezolizumab in multiple indications.
AFM28 is an ICE® that targets CD123 on leukemic cells and CD16A on NK cells, thereby mediating NK cell induced antibody-dependent cellular cytotoxicity (ADCC). It is being developed for patients with CD123-expressing hematological malignancies, including acute myeloid leukemia (AML), who are in need of new therapeutic options, because they are either primary refractory to or have relapsed after treatment. AML treatment failures are attributed to the persistence of leukemic stem cells (LSCs), a subpopulation of AML cells with self-renewal and leukemia-initiating capacities, which have been shown to be highly refractory to conventional antileukemic treatments and are believed to be the fundamental cause of drug resistance and AML relapse. Therefore, effective depletion of leukemic blasts as well as eradication of residual LSCs is crucial for long-term remission. AFM28 was shown to efficiently induce lysis of CD123-positive leukemic cell lines and to control the tumor outgrowth in an in vivo mouse model of AML. Additionally, AFM28 mediated strong NK cell-dependent depletion of both CD123-positive leukemic blasts and LSCs from AML patient samples thereby exhibiting a capacity to induce long-term remission, and preventing disease relapse after conventional treatment or allogeneic stem cell transplant in patients with AML .12
A first-in-human Phase 1 clinical study has been initiated in 2023 and development in combination with allogeneic NK cell therapy is planned.
Preclinical data of AFM24 indicate promising efficacy across a wide variety of solid tumor types, including, but not limited to lung, colon, renal, and gastric cancers.8 Clinical data are currently being generated, and if successful, AFM24 could address a significant patient population underserved by current therapies. Emerging clinical data of acimtamig demonstrate impressive efficacy across a number of lymphoma types, including T-cell lymphoma and Hodgkin lymphoma.5,7
We are awaiting highly anticipated results in several EGFR-expressing tumors (eg, lung, RCC, CRC), T-cell lymphoma, Hodgkin lymphoma, and additional CD30-positive lymphomas.
Affimed’s ICE® (innate cell engager) molecules are built on the ROCK® platform—the most clinically advanced technology for designing innate immunity therapies that can be tailored to specific patient populations, allowing for the creation of powerful monotherapies and I-O combination treatments.
ADCC=antibody-dependent cellular cytotoxicity; cbNK=cord blood–derived natural killer cell; CD=cluster of differentiation; CR=complete response; CRC=colorectal cancer; EGFR=epidermal growth factor receptor; I-O=immuno-oncology; IgG=immunoglobulin G; MOA=mechanism of action; NK=natural killer; ORR=objective response rate; PD-1=programmed cell death protein 1; RCC=renal cell carcinoma.
References: 1. Ellwanger K, Reusch U, Fucek I, et al. Redirected optimized cell killing (ROCK®): A highly versatile multispecific fit-for-purpose antibody platform for engaging innate immunity. MAbs. 2019;11(5):899-918. 2. Wingert S, Reusch U, Baez A, et al. CD16A-specific tetravalent bispecific immuno-engagers potently induce antibody-dependent cellular phagocytosis (ADCP) by macrophages. Poster presented at: American Society of Hematology (ASH) Annual Meeting; December 1-4, 2018; San Diego, CA. 3. Zhao X, Rajasekaran N, Reusch U, et al. In vitro and in vivo characterization of CD19/CD3 Tandab AFM11 and CD19/CD16A Tandab AFM12 targeting NHL. Poster presented at: American Society of Hematology (ASH) Annual Meeting; December 5-8, 2015; Orlando, FL. 4. Rothe A, Sasse S, Topp MS, et al. A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2015;125(26):4024-4031. 5. Kim WS, Shortt J, Zinzani PL, et al. REDIRECT: A Phase 2 study of AFM13 in patients with CD30-positive relapsed or refractory (R/R) peripheral T cell lymphoma (PTCL). AACR 2023. CT024. https://www.aacr.org/wp-content/uploads/2023/05/AACR2023_LBA-Trials_AbstractsEbook.pdf 6. Sawas A, Chen P, Vlad G, et al. Clinical and biological evaluation of the novel CD30/CD16A tetravalent bispecific antibody (AFM13) in relapsed or refractory CD30-positive lymphoma with cutaneous presentation: a biomarker Phase Ib/IIa study (NCT03192202). Poster presented at: American Society of Hematology (ASH) Annual Meeting; December 1-4, 2018; San Diego, CA. Final data available here: History of Changes for Study: NCT03192202 (clinicaltrials.gov). 7. Bartlett NL, Herrera AF, Domingo-Domenech E, et al. A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2020;136(21):2401-2409. 8. Nieto Y, Banerjee PP, Kaur I, et al. Presentation at ASH Annual Meeting 2022. Abstract: Blood (2022) 140 (Supplement 1): 415–416. 9. Wingert S, Reusch U, Knackmuss S et al. Preclinical evaluation of AFM24, a novel CD16A-specific innate immune cell engager targeting EGFR-positive tumors. mAbs. 2021;13(1): e1950264. 10. El-Khoueiry A, Lopez J, Saavedra O et al. A Phase 1/2a Dose Escalation Study of AFM24 in Patients With Epidermal Growth Factor Receptor-Expressing (EGFR) Solid Tumors: Results From Phase 1. Poster presented at: European Society for Medical Oncology (ESMO) Annual Congress; June 9-13, 2022. Poster 754P. 11. Hintzen G, Wingert S, Emig M, et al. Targeting Epidermal Growth Factor Receptor (EGFR)-Expressing Solid Tumors With AFM24, A Novel CD16A Bispecific Innate Cell Engager: Comprehensive Correlative Science Findings From A Phase 1 Study. Poster presented at: Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting; November 8-12, 2022. Poster 729. 12. Schmitt N, Siegler J-J, Wagner L, et al. The Novel Bispecific Innate Cell Engager (ICE®) AFM28 Efficiently Directs Allogeneic NK Cells to CD123-positive leukemic cells. Poster presented at: American Society of Hematology (ASH) Annual Meeting; December 10-13, 2022; New Orleans, Louisiana.